Pathophysiology of Atherosclerosis



Ci a ion: Jeba i-Benslaiman, S.;
Galicia-Ga cía, U.; La ea-Sebal, A.;
Olae xea, J.R.; Alloza, I.;
Vandenb oeck, K.; Beni o-Vicen e, A.;
Ma ín, C. Pa hophysiology o
A he oscle osis. In . J. Mol. Sci. 2022,
23, 3346. h ps://doi.o g/10.3390/
ijms23063346
Academic Edi o : Man edi Rizzo
Recei ed: 3 Decembe 2021
Accep ed: 18 Ma ch 2022
Published: 20 Ma ch 2022
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In e na ional Jou nal o
Molecula Sciences
Re iew
Pa hophysiology o A he oscle osis
Shi a Jeba i-Benslaiman 1,2, Unai Galicia-Ga cía2,3, Asie La ea-Sebal 2,3, Ja ie Rekondo Olae xea 4,
I aide Alloza 1,5, Koen Vandenb oeck 1,5,6, Asie Beni o-Vicen e 1,2,* and Césa Ma ín1,2,*
1Depa men o Biochemis y and Molecula Biology, Uni e sidad del País Vasco UPV/EHU,
48940 Leioa, Bizkaia, Spain; [email p o ec ed] (S.J.-B.); [email p o ec ed] (I.A.);
[email p o ec ed] (K.V.)
2Bio isika Ins i u e (UPV/EHU, CSIC), Ba io Sa iena s/n., 48940 Leioa, Bizkaia, Spain;
[email p o ec ed] (U.G.-G.); [email p o ec ed] (A.L.-S.)
3Fundación Bio isika Bizkaia, Ba io Sa iena s/n., 48940 Leioa, Bizkaia, Spain
4Ca diology Depa men , Basu o Uni e si y Hospi al, 48013 Bilbao, Bizkaia, Spain;
ja ie g ego io. [email p o ec ed]
5In lamma ion & Bioma ke s G oup, Bioc uces Bizkaia Heal h Resea ch Ins i u e,
48903 Ba akaldo, Bizkaia, Spain
6Ike basque, Basque Founda ion o Science, 48013 Bilbao, Bizkaia, Spain
*Co espondence: asie [email p o ec ed] (A.B.-V.); cesa [email p o ec ed] (C.M.); Tel.: +34-946-01-2741 (C.M.)
Abs ac :
A he oscle osis is he main isk ac o o ca dio ascula disease (CVD), which is he
leading cause o mo ali y wo ldwide. A he oscle osis is ini ia ed by endo helium ac i a ion and,
ollowed by a cascade o e en s (accumula ion o lipids, ib ous elemen s, and calci ica ion), igge s
he essel na owing and ac i a ion o in lamma o y pa hways. The esul an a he oma plaque, along
wi h hese p ocesses, esul s in ca dio ascula complica ions. This e iew ocuses on he di e en
s ages o a he oscle osis de elopmen , anging om endo helial dys unc ion o plaque up u e. In
addi ion, he pos - ansc ip ional egula ion and modula ion o a he oma plaque by mic oRNAs and
lncRNAs, he ole o mic obio a, and he impo ance o sex as a c ucial isk ac o in a he oscle osis
a e co e ed he e in o de o p o ide a global iew o he disease.
Keywo ds:
a he oscle osis; endo helial dys unc ion; a he oma plaque; isk ac o s; mic obio a;
ocLDL; mic oRNA; lncRNA
1. In oduc ion
A he oscle osis is a disease ha is cha ac e ized by he accumula ion o lipids, ib ous
elemen s, and calci ica ion wi hin he la ge a e ies. This p ocess is ini ia ed by endo helium
ac i a ion, ollowed by a cascade o e en s, which implies he essel na owing and
ac i a ion o in lamma o y pa hways leading o a he oma plaque o ma ion. Al oge he ,
hese p ocesses esul in ca dio ascula complica ions ha emain as he leading cause o
dea h wo ldwide.
In his s udy, we aimed o e iew he mechanism o de elopmen o a he oscle osis,
including endo helial dys unc ion, a y s eak o ma ion, ib ous plaque o ma ion, and
plaque up u e. This e iew app oaches he pa hophysiology o a he oscle osis om a
b oad pe spec i e, examining he pa hological and biochemical p ocesses o a he oscle-
o ic plaque o ma ion and g ow h. In addi ion, his e iew summa izes he cu en
unde s anding o he in ol emen o mic oRNAs and lncRNAs in pos - ansc ip ional
egula ion and modula ion o a he oma plaque and a he ogenesis. Non- adi ional d i e s
o a he oscle osis—such as dis u bed sleep, physical inac i i y, he mic obiome, he ole o
mic obio a, and he impo ance o sex as a c ucial isk ac o in a he oscle osis a e co e ed
he e in o de o p o ide a global iew o he disease.
In . J. Mol. Sci. 2022,23, 3346. h ps://doi.o g/10.3390/ijms23063346 h ps://www.mdpi.com/jou nal/ijms
In . J. Mol. Sci. 2022,23, 3346 2 o 38
2. Endo helium
The ascula endo helium is a he e ogeneous monolaye o med by endo helial cells
(ECs), which ace he luminal side o all blood essels, ep esen ing he i s ba ie o
molecules, cells, o pa hogens ci cula ing in he bloods eam [
1
]. In la ge essels, he
essel wall is lined wi h a single EC laye called he endo helium, which, oge he wi h
collagen and elas ic ibe s, o ms he luminal laye o he essels o he in ima. ECs a e in
in ima e con ac wi h unica media consis ing o ascula smoo h muscle cells (VSMC) and
elas ic and collagenous issue. Finally, su ounding his laye is unica ad en i ia, which is
composed mainly o a dense ma ix o connec i e issue. On he o he hand, he walls o
a e ioles and enules a e composed o he same h ee laye s as he la ge essels, al hough
he media and ad en i ia a e much hinne and less p onounced. Finally, pos -capilla y
enules comple ely lack media and ad en i ia and only consis o ECs and a basemen
memb ane [2].
Endo helium is s a egically loca ed be ween ci cula ing blood and issues, wo king as
a senso and ansduce o signals by he p oduc ion o biologically ac i e subs ances. All
changes in ci cula ing blood a e pe cei ed by he endo helium, which hen media es signal
ansduc ion o he o he laye s o he ascula wall. Such changes include mechanical
s ess (elonga ion and wall shea s ess (WSS)), as well as changes in he concen a ion o
me abolic ac o s.
Di e en mechanical o ces ac ing on he a e ial wall modula e se e al physiological
unc ions, such as he egula ion o homeos asis, ascula one, and ascula in eg i y.
Apa om hei ole in homeos asis, he in ol emen o hemodynamics in ascula disease
de elopmen has been shown o be c ucial in he pa hology o a he oscle osis, a ec ing
bo h disease onse and p og ession. The main o ces ac ing on he a e ial wall include
bo h ensile s ess induced by blood p essu e and WSS, a angen ial o ce o he essel wall
induced by blood low ha plays an impo an ole in a he ogenic hemodynamics [3].
Vessel segmen s wi h low WSS o highly oscilla o y WSS appea o be a he highes
isk o de elopmen o a he oscle osis [
4
,
5
]. WSS change can di ec ly a ec he mo phology
and unc ion o he ascula endo helium and s imula e he mig a ion and p oli e a ion o
VSMCs and mononuclea cells [
6
]. Whe he low o uns able, changing WSS is an indica o
o e alua e hemodynamic changes ha a e closely ela ed o a he oscle osis [7,8].
The magni ude and di ec ion o WSS a e ecognized by mechanosenso s on he en-
do helium and a e ansduced as biochemical signaling. WSS-induced mechano ansduc-
ion egula es he exp ession o nume ous genes in ol ed in cell mo phology, adhesion,
and p oli e a ion.
Fo example, shea s ess induces cha ac e is ic EC alignmen [
9
,
10
] (Figu e 1A). In
ubula o s aigh egions o a e ies, whe e he WSS p esen s a lamina low, ECs show a
la ened shape and an elonga ed alignmen in he di ec ion o he low [
11
]. Howe e , a
he bi u ca ion o high essel cu a u e si es, low dis u bance occu s and, as a consequence
o he u bulen and e e sal low wi h lowe ed WSS a he ou e essel wall, ECs augmen
hei olume by adop ing a cobbles one appea ance [
12
] (Figu e 1A). Mo eo e , hemody-
namic o ces de e mine he ea ly de elopmen o localized a he oscle o ic plaques ha a e
no andomly dis ibu ed, nei he in expe imen al animal models no in humans [
13
,
14
].
A he oscle o ic lesions mainly occu in egions cha ac e ized by low WSS and low sepa a-
ion (Figu e 1B) and mos equen ly in ol e b anch poin s and bi u ca ions. The ex ensi e
co ela i e da a indica ing ha low shea o dis up ed low accoun s o he localiza ion
o a he oscle osis lesions emphasize he impo ance o a e ial b anches and bi u ca ions
when pe o ming a diagnosis o a he oscle o ic lesion de elopmen o p og ession.
In . J. Mol. Sci. 2022,23, 3346 3 o 38
Figu e 1.
E ec o low and WSS pa e ns a a e ial bi u ca ions on a he oscle o ic plaque de elop-
men . (
A
) In s aigh essel segmen s, physiological WSS wi h lamina low leads o ECs and shows a
quiescen cha ac e is ic la ened shape when low dis u bance occu s. Lowe WSS a he ou e essel
wall causes ECs o adop a cobbles one appea ance. (
B
) Tu bulen low occu s a bi u ca ions and
b anch poin s whe e he a e ial cu a u e is highe due o low sepa a ion. Dis u bed lamina low
o u bulen low educes WSS and p omo es endo helial dys unc ion and LDL in il a ion, which
cons i u es he i s s ep o a he oma plaque o ma ion. On he con a y, low cu a u e a eas o he
ascula sys em subjec ed o highe shea s ess a e a he o-p o ec ed.
Endo helium modula es he one o unde lying ascula smoo h muscle; main ains a
non-adhesi e luminal su ace; and media es hemos asis, cellula p oli e a ion, and in lam-
ma o y and immune esponse in he ascula wall [
15
]. In ac , endo helium eleases bo h
agonis s and an agonis s in o de o balance he e ec in bo h di ec ions. Fo ins ance, ECs
a e able o p oduce bo h coagulan s o an i-coagulan s, asodila o s o asocons ic o s
and p o-in lamma o y o an i-in lamma o y molecules [15,16].
3. A he oscle osis Ini ia ion and Fa y S eak Fo ma ion
A he oscle osis ini ia es upon endo helial dys unc ion accompanied by low-densi y
lipop o ein (LDL) e en ion and i s modi ica ion in he in ima [
17
,
18
]. Modi ied LDLs,
In . J. Mol. Sci. 2022,23, 3346 4 o 38
oge he wi h addi ional a he ogenic ac o s, p omo e he ac i a ion o ECs, leading o
monocy e ec ui men wi hin he in ima. Modi ied LDLs a e a idly cap u ed by di e -
en ia ed monocy es and VSMC, which p omo e oam cell o ma ion [
19
,
20
]. In addi ion,
se e al in lamma o y signaling pa hways a e ac i a ed, allowing he a y s eak o ma ion,
which ep esen s he i s sign o a he oscle osis and is cha ac e ized by a subs an ial ac-
cumula ion o lipids bo h wi hin he cells (mac ophages and VSMC) and he ex acellula
media [21].
3.1. Endo helial Dys unc ion in A he oscle osis De elopmen
Dis up ion o he mechanisms in ol ed in ascula homeos asis egula ion leads o
endo helial dys unc ion [
9
,
12
,
22
]. B ie ly, when ECs lose hei abili y o main ain homeos a-
sis, essel walls a e p edisposed o asocons ic ion, lipid in il a ion, leukocy e adhesion,
pla ele ac i a ion, and oxida i e s ess, among o he hings [
23
,
24
]. Toge he , hese induce
an in lamma o y esponse ha is conside ed he i s s ep o a he oma ous plaque o ma-
ion: he a y s eak [
12
,
22
]. In addi ion, endo helial dys unc ion also plays a ema kable
ole in subsequen s eps o a he oscle osis by pa icipa ing in plaque de elopmen and
in i s up u e in he las s eps o a he oscle osis [
22
]. The e o e, an inc eased endo helial
dys unc ion is conside ed an ea ly indica o o a he ogenesis [25,26].
3.1.1. Hemodynamic Fo ces and Endo helial Dys unc ion
Hemodynamic o ces cons i u e a local isk ac o o a he ogenesis, as hey p omo e
endo helial dys unc ion [27]. As indica ed abo e, lesion-p one egions a e mainly loca ed
in a eas whe e he lamina low is dis u bed due o low sepa a ion, eci cula iza ion, o
ea achmen [
28
]. This u bulen low c ea es empo al and spa ial g adien s, which esul
in a highe oscilla o y index and a lowe shea s ess [
11
,
29
]. In addi ion, a dis u bed low
also a o s lipop o ein in il a ion in o he essel in ima, i s ly because LDLs emain in
hose a eas o longe pe iods o ime, and secondly because u bulen low induces a
physical dis up ion o endo helial in eg i y [
30
,
31
], hus acili a ing lipop o ein in il a-
ion [
30
,
32
,
33
]. In addi ion, ano he undamen al link be ween hemodynamic o ces and
a he ogenesis elies on he exp ession o di e se endo helial genes egula ed by blood
mechanical s imulus [34–36].
The e ec o shea s ess o e endo helial gene exp ession has been s udied du ing
he las 20 yea s; mo e han 40 genes implica ed in he p ocess ha e been disco e ed so
a [37–42].
Among hem, se e al a he ogenic genes, such as monocy e chemoa ac an
p o ein 1 (MCP-1), which induces monocy e pe mea ion in o he a e ial wall [
43
–
45
],
and pla ele -de i ed g ow h ac o s (PDGFs), which enhance VSMC mig a ion [
46
–
48
], a e
up egula ed in ECs. In e es ingly, esea ch e idence e ealed shea s ess esponse elemen s
(SSREs) in he p omo e s o hese genes and o he s, such as eNOS o pla ele adhesion
molecule-1 (PECAM-1), which con ibu e o plaque de elopmen [
49
–
52
]. Mo eo e , he
combina ion o wo o mo e SSREs in he same p omo e could ha e a syne gis ic e ec
ha enhances he exp ession o hose genes [
53
]. On he o he hand, in s aigh egions o
he ascula u e whe e he lamina low d i es high shea s ess in he endo helium, some
p o-a he ogenic genes a e down egula ed, while genes ha induce cell-cycle g ow h a es
o inc ease he an ioxidan capaci y a e up egula ed. Indeed, a long exposu e o ECs o
undis u bed lamina low p omo es he up egula ion o endo helial ni ic oxide syn hases
(eNOSs), hus inc easing hei ni ic oxide (NO) syn hesis capaci y [13,49].
These indings sugges a di e en ial molecula esponse in endo helium depending
on he blood low pa e n, highligh ing he ole o hemodynamic o ces in endo helial
dys unc ion.
3.1.2. The Role o Ni ic Oxide in Endo helial Dys unc ion
Endo helial dys unc ion is also explained h ough a educ ion in NO bioa ailabil-
i y [
54
]. NO is syn hesized om L-a ginine in ECs in a eac ion ca alyzed by eNOS and
di uses ac oss cell memb anes, eaching he smoo h muscle issue o he a e y wall.
In . J. Mol. Sci. 2022,23, 3346 5 o 38
NO p omo es smoo h muscle ibe elaxa ion, known as endo helium-dependen asodi-
la a ion [
55
,
56
], and is conside ed an a he o-p o ec i e molecule, because i coun e ac s
a he ogenesis and i s complica ions. Speci ically, NO is in ol ed in he educ ion o pla ele
agg ega ion; issue oxida ion and in lamma ion; he ac i a ion o h ombogenic ac o s; and
cell g ow h, p oli e a ion, and mig a ion, among o he hings [
57
–
60
] (Figu e 2). Mo eo e ,
i main ains me abolic homeos asis, as i educes iglyce ide con en and s ea osis and
inc eases insulin syn hesis, glucose clea ance, and mi ochond ial e iciency [
61
]. How-
e e , in he p esence o ca dio ascula isk ac o s, such as hype lipidemia, hype ension,
smoking, o diabe es, NO p oduc ion is educed as a consequence o he inc eased oxida-
i e s ess, which is commonly associa ed wi h hose pa hologies [
28
,
62
,
63
]. Oxida i e
s ess p omo es he syn hesis o p o-a he ogenic cy okines (TNF-
α
and in e leukins IL-1
and IL-6), adhesion molecules (VCAM-I and ICAM-I), and chemokines (MCP-1) h ough
NF-kB ac i a ion media ed by hea -shock p o eins (HSP-60). These media o s inhibi he
ac i i y o eNOS and, consequen ly, NO p oduc ion [
12
] (Figu e 2). In ac , s udies ca ied
ou in hype choles e olemic pa ien s demons a ed an impai ed endo helium-dependen
asodila a ion due o a de ec in he bioa ailabili y o NO [
64
]. Hype ensi e pa ien s
also show a de ec in he endo helium-de i ed NO sys em ha may explain he abno mal
endo helium-dependen asodila a ion [65,66].
Figu e 2.
Ni ic oxygen egula es ca dio ascula me abolism and is comp omised in he p esence o
ca dio ascula isk ac o s. eNOS ca alyzes he p oduc ion o NO om L-a ginine. NO is an essen ial
me aboli e ha inhibi s he p og ession o a he oscle osis imp o ing aso elaxa ion, angiogenesis,
endo helial unc ion, insulin sec e ion, glucose clea ance, and mi ochond ial e iciency. On he o he
hand, i educes oxida i e s ess, in lamma ion, plasma lipid le els, and s enosis. Ca dio ascula
isk ac o s, such as hype lipidemia, hype ension, and diabe es, inhibi eNOS ac i i y upon NF-k
β
induc ion, educing NO and p omo ing a he oscle osis de elopmen .
3.2. LDL In il a ion
Accumula ion o LDL in plasma a o s ansendo helial in il a ion o ci cula ing
LDLs o he in ima. Al hough i has been adi ionally accep ed ha LDLs c oss he
endo helium by di usion o pa acellula ly [
67
–
70
], i is now accep ed ha anscy osis
plays an impo an ole in he ansendo helial anspo o LDLs [
71
,
72
]. Mo e speci ically,
i has been shown ha LDL anscy osis is media ed by sca enge ecep o B1 (SR-B1)
and ac i in A ecep o -like ype 1 (ALK1) ecep o o he endo helium, which di e s
om he classical LDL endocy osis pa hway media ed by LDLR [
73
]. SR-B1 and ALK1
ecep o s co-localize wi h ca eolae, indica ing ha LDL anscy osis by SRB1 and ALK1 is
media ed by a ca eolae-dependen mechanism [
74
,
75
]. Mo eo e , an absence o ca eolin-1,

In . J. Mol. Sci. 2022,23, 3346 6 o 38
he majo s uc u al p o ein o ca eolae in ECs [
76
], signi ican ly impai s LDL anspo
and e en ion wi hin he a e ial wall [
77
,
78
], and inc eased le els o ca eolin-1 ha e been
ound in a he oscle o ic lesions [
79
]. Al hough addi ional expe imen s a e needed o
elucida e he speci ic anspo mechanism o bo h ecep o s, hese indings sugges ha
ca eolae-dependen LDL up ake plays an impo an ole in LDL anscy osis [80,81].
Al hough his e iew only summa izes he ole o ECs in LDL in il a ion, i is impo -
an o no e ha o he ac o s, such as he glycocalyx [
82
], pe icy es [
83
], he subendo helial
ex acellula ma ix [84,85], and he ole o shea s ess [32], should be conside ed.
LDL Modi ica ions in he In ima
Once in he subendo helial space, apped LDL pa icles a e oxidized, a p ocess
acili a ed by he absence o p o ec i e plasma an ioxidan s, such as ocophe ol, asco ba e,
u a e, apolipop o eins, o se um albumin [
86
,
87
]. Oxidized LDLs a e key in lamma o y
componen s ha p omo e a he oscle o ic plaque de elopmen , as hey con ain oxidized
lipids and p oduc s de i ed om hei deg ada ion ha con ibu e o he physiopa hology
o he disease [88,89].
LDLs can be oxidized by ee adicals p esen in he ex acellula media, such as
supe oxide (O
2•–
), hyd oxyl adicals (
•
OH) [
90
], and o he s, such as HClO, p oduced by
he su ounding cells [
91
,
92
]. Addi ionally, LDLs can be di ec ly oxidized by he enzyma ic
ac i i y o phospholipases and lipoxygenases [
93
,
94
]. In ac , he lipoxygenase pa hway
has been highligh ed o explain he ini ia ion o LDL oxida ion [
95
]. In e es ingly, LDL
ecep o - ela ed p o ein (LRP) is in ol ed in LDL ec ui men , and 12/15 lipoxygenase is
ansloca ed o he memb ane whe e oxida ion o LDL choles e ol es e s akes place [94].
Independen o he mechanism in ol ed in he ini ia ion o he LDL oxida ion, he
p ocess is cha ac e ized by he loss o he an ioxidan s ca ied by LDLs, including alpha-
ocophe ol and ca o enoids [
96
,
97
]. This is ollowed by he small deg ada ion o polyunsa -
u a ed a y acids (PUFAs), mos ly a achidonic and linoleic acids, which a e oxidized o
hyd ope oxides. The la e leads o he o ma ion o conjuga ed dienes and, upon u he
oxida ion, sho -chain aldehydes [98].
On he o he hand, apoB-100, he majo p o ein o he LDL, also su e s di e en modi-
ica ions as a consequence o he oxida i e en i onmen . Fo ins ance, aldehydes gene a ed
om lipid oxida ion o m adduc s wi h lysine esidues o apoB-100. Ins ead, apoB-100 can
be di ec ly modi ied p edominan ly a y osine esidues by oxidizing agen s [
99
]. These
modi ica ions inhibi LDL-LDLR ecogni ion, hus inc easing he up ake o LDL pa icles
h ough non- egula ed ecep o s [87].
Depending on he LDL oxida ion le el, oxidized LDLs a e classi ied as minimally
modi ied LDL (mmLDL) o ex ensi ely oxidized LDL (oxLDL) [
100
]. Mm-LDLs di e
chemically om unmodi ied LDLs bu a e s ill ecognizable by he LDLR and he e o e a e
in e nalized h ough egula ed pa hways. Howe e , modi ied lipids wi hin hese pa icles
ac as bioac i e molecules con e ing o he biological ac i i ies no shown in unmodi ied
LDLs [
100
,
101
]. These bioac i e lipids migh induce a p o-in lamma o y esponse in ECs
and mac ophages [
102
–
104
]. On he o he hand, when LDLs a e ex ensi ely modi ied, hey
become un ecognizable by he LDLR, while allowing ecogni ion by a ange o sca enge
ecep o s [
105
–
108
]. Oxida i e modi ica ions o apoB-100 unde lie his lack o a ini y
owa d LDLR and he inc eased a ini y o he sca enge ecep o s. Mo eo e , oxLDLs a e
able o escape om p o eoglycan e en ion, hence a o ing hei non- egula ed up ake by
sca enge ecep o s [
84
,
109
]. Once in e nalized, p oduc s de i ed om oxLDL igge he
exp ession o in lamma o y molecules in mac ophages, as ou lined la e in his e iew.
I is impo an o no e ha , e en wi h LDL oxida ion being he mos common modi-
ica ion, a ange o LDL modi ica ions con ibu ing o a he oscle osis de elopmen ha e
been well desc ibed in o he wo ks, including glycosyla ion, ace yla ion, and agg ega-
ion [107,110–113].
In . J. Mol. Sci. 2022,23, 3346 7 o 38
3.3. Endo helial Ac i a ion
Endo helial s imula ion, also known as endo helial ype I ac i a ion, occu s when
in lamma o y agen s induce a esponse such as a change in mic o ascula one, pe me-
abili y, o leukocy e diapedesis [
114
,
115
]. This phenomenon is an acu e esponse wi h
sho - e m unc ional and mo phological changes and does no equi e de no o p o ein
syn hesis o gene up egula ion [
115
]. Howe e , in esponse o ce ain p oin lamma o y
agen s, such as IL-1, TNF, endo oxins, modi ied lipop o eins, and ad anced glycosyla ion
end p oduc s (AGE), as well as dis u bed low de i ed biomechanical s imula ion, he
endo helium can unde go a sus ained pheno ypic modula ion, known as endo helium
ype II ac i a ion [
114
,
115
]. This ac i a ion leads o a complex in lamma o y esponse ha
s a s wi h an inc eased NF-kB p oduc ion wi hin he ECs, in esponse o he a o emen-
ioned s imulus. NF-kB up egula es he exp ession o leucocy e adhesion molecules, such
as VCAM-1 and ICAM-1; sec e ed chemokines, such as MCP-1 and IL-8 [
116
,
117
]; and
p o h ombo ic media o s, such as plasminogen ac i a o inhibi o o issue ac o .
3.4. Monocy e Rec ui men and Foam Cell Fo ma ion
Ac i a ed ECs induce selec i e monocy e ec ui men in o he in ima. This p ocess has
been isualized
in i o
[
118
], and i can be summa ized in he olling, adhesion, ac i a ion,
and ansmig a ion o monocy es, as has been well documen ed [119–121].
B ie ly, monocy e ec ui men s a s wi h monocy e cap u e and olling o e he en-
do helium, which is mainly media ed by P-selec in [
122
,
123
]. Monocy e- olling is hen
educed, and monocy es emain i mly a ached o he endo helium [
124
], a p ocess medi-
a ed by he binding o monocy es in eg ins o VCAM-I and ICAM-I o ECs [
123
,
125
,
126
].
In addi ion, while olling o e he endo helium, monocy es a e ac i a ed by endo helial
su ace-bound chemokines [
127
], such as CXCL1, CXCL2, CXCL4, and CCL5, and his
inc eases monocy e adhesi eness [
124
]. A e wa d, monocy es ansmig a e in o he in ima
space. This mo emen comp ises he c ossing h oughou he EC ba ie , i s basemen
memb ane, and he pe icy e laye [
123
,
128
]. The mig a ion p ocess is held by chemokines,
which ha e been p e iously sec e ed in esponse o p oin lamma o y signals.
Rega ding monocy e ec ui men , MCP-1 (also named as CCL2) is he mos equen
chemokine media ing monocy e ansmig a ion; howe e , he e ec o o he chemokines,
such as CCL3, CCL4, and CCL5, has also been s udied [
129
,
130
]. MCP-1 is p oduced
mainly by ECs, smoo h muscle cells, and monocy es and mac ophages o he in ima, and
i s exp ession is up egula ed a e p oin lamma o y s imulus o issue inju y, a o ing he
ansendo helial mig a ion o ci cula ing monocy es om he plasma o he in ima [
131
].
This p ocess is media ed by he pa acellula and anscellula ou es [
120
,
123
,
132
]. In
he pa acellula ou e, monocy e mig a ion is a o ed h ough EC junc ions, due o he
edis ibu ion o junc ional molecules in he in lamed endo helium [
133
,
134
]. In addi ion,
some endo helial junc ion molecules ac i ely media e his ype o mig a ion [
135
,
136
]. On
he o he hand, in he anscellula ou e, cells mig a e h ough he body o ECs; howe e ,
his ype o ansmig a ion has been obse ed in only 10–30% o he e en s
in i o
[
137
,
138
].
New ad ances in li e cell imaging will cla i y his ield [
118
,
139
]. Finally, monocy es c oss
he EC basemen memb ane, which is composed o a ne wo k o laminin and collagen, and
he pe icy e shea h, which is ound in mos enules [132,140].
Once in he in ima, monocy es a e di e en ia ed in o mac ophages ha can be po-
la ized o he M1 (p o-in lamma o y) o M2 (an i-in lamma o y) pheno ype [
141
,
142
].
None heless, mac ophages show sensi i i y o he changes in in lamma o y en i on-
men , and, in esponse o new signals, hey a e able o swi ch hei pheno ype om
p o-in lamma o y o an i-in lamma o y [
143
–
145
]. Mac ophage plas ici y is undamen al
o a success ul esponse wi h M1 p edomina ing in disease p og ession and M2 in e-
g ession [142,146]. M1 mac ophages elease in lamma o y cy okines and chemokines and
p oduce NO and eac i e oxygen species (ROS), which p omo e monocy e ec ui men and
in lamma o y esponse p opaga ion [
144
]. In addi ion, mac ophages exp ess a ba e y o e-
cep o s ha media e he in e naliza ion o modi ied and non-modi ied LDLs. As p e iously
In . J. Mol. Sci. 2022,23, 3346 8 o 38
men ioned, e ained lipop o eins in he in ima a e p one o su e modi ica ions due o he
in lamma o y en i onmen , allowing hei in e naliza ion h ough CD36, SRA-l, and LOX-I
sca enge ecep o s [
105
–
107
]. I is impo an o unde line ha he exp ession o hose
ecep o s is no down egula ed by choles e ol up ake. Thus, in an a he oscle o ic con ex ,
whe e oxLDL con en is signi ican ly enhanced, cells in e nalize highe amoun s o oxLDLs.
Wi hin he cells, oxLDLs a e deg aded in he lysosomes, and he lipop o ein-con ained
choles e ol is es e i ied by acyl CoA:choles e ol acyl ans e ase (ACAT) in he endoplasmic
e iculum (ER). Choles e ol es e s a e s o ed as lipid d ople s loca ed bo h in he cy oplasm
o linked o he ER [
147
,
148
]. Hyd olysis o hese packed choles e ol es e s media ed by
neu al choles e ol es e hyd olases, such as nCEH and NCEH1, gene a es ee choles e ol
ha is ans e ed om mac ophages o apoA1 o HDLs (high-densi y lipop o ein), an
impo an s ep o he emo al o choles e ol excess om pe iphe al issues [
149
]. This
p ocess is media ed by ABCA1 and ABCG1 ATP-binding casse es and SR-B1, choles e ol
anspo e s ha play an impo an ole media ing choles e ol e lux om he cells and
p e en ing oam cell o ma ion [
105
]. Howe e , he p o-in lamma o y mic oen i onmen o
a he oscle o ic lesions impai s he ABCA1 e lux sys em, bo h in M1 and M2 mac ophages,
and p omo es oam cell accumula ion, as shown in expe imen s wi h mu ine mac ophages
con ibu ing o plaque de elopmen [150,151].
In addi ion, he excess o lipid up ake by mac ophages pe pe ua es he in lamma o y
esponse, and oxLDLs induce signaling cascades ha ac i a e NF-kB a ge s [
152
–
154
],
which main ain EC ac i a ion, monocy e ec ui men , and oam cell o ma ion [
146
]. The
up ake o oxLDLs by mac ophages could be conside ed a p o ec i e mechanism, as hey
emo e cy o oxic elemen s om he in ima. Howe e , he inc eased mig a ion o monocy e
o he in ima and he subsequen di e en ia ion in o mac ophages lead o a la ge numbe
o oam cells inducing he g ow h o he a he oscle o ic lesion [
147
]. The e o e, choles e ol
accumula ion is conside ed a hallma k o a he oscle o ic lesions [155,156].
An accumula ion o choles e ol in he subendo helial compa men also p omo es he
o ma ion o choles e ol c ys als bo h inside and ou side he cells and con ibu es o he
de elopmen o a he oscle o ic plaques [
157
–
159
]. This p ocess has been moni o ed bo h
ou side and inside he cells, in mac ophages incuba ed wi h oxLDLs [
160
]. Al hough choles-
e ol c ys als a e a common ea u e o ad anced a he oscle o ic lesions, hey a e p esen also
in ea ly plaques and can be used as a ma ke o ea ly a he oscle osis de elopmen [
161
].
Choles e ol c ys als wi hin he plaque ac i a e NLRP3 in lammasome in mac ophages, lead-
ing o ac i a ion o p o-in lamma o y pa hways. In lammasomes a e cy osolic mul ip o ein
complexes o he inna e immune sys em esponsible o he ac i a ion o in lamma o y
pa hways [
162
]. Al hough NLRP3 ac i a ion and assembly is no ully unde s ood, i is
known ha i s ac i a ion leads o caspase-1 ac i a ion. Caspase-1 subsequen ly clea es
he p oin lamma o y IL-1 amily o cy okines in o hei bioac i e o ms, IL-1
β
and IL-18,
con ibu ing o in lamma ion [
88
]. I has been sugges ed ha up ake o oxLDLs media ed
by he CD36 ecep o is esponsible o NLRP3 ac i a ion [
88
]. Appa en ly, he CD36
sca enge ecep o , along wi h TLR4-TLR6, akes up oxLDL, which esul s in in acellula
choles e ol c ys als. These c ys als cause lysosomal des abiliza ion [
163
], inducing he
elease o lysosomal con en s, such as ca hepsins o eac i e oxygen species [
164
], leading
o NLRP3 in lammasome assembly and he subsequen ac i a ion o caspase-1.
3.5. Con ibu ion o VSMCs o Foam Cell Popula ion
VSMCs loca ed in he in ima a e also able o in e nalize oxLDL in a non- egula ed way
h ough di e en sca enge ecep o s, such as SR-A, CD36, and LOX-1 [
165
–
169
]. Indeed,
hei con ibu ion o he sum o oam cell popula ion wi hin he plaque is signi ican [
20
].
In addi ion, VSMCs o he in ima exp ess ewe ABCA1 anspo e s han he ones o he
unica media [
170
]. The e o e, he balance be ween choles e ol inpu and ou pu is il ed in
a o o choles e ol accumula ion and oam cell o ma ion. A leas 50% o he oam cells in
he human co ona y in ima a e VSMC-de i ed a he han monocy e-de i ed, unde lying
he impo ance o VSMCs in a he oscle osis de elopmen [170].
In . J. Mol. Sci. 2022,23, 3346 9 o 38
4. Fib ous Plaque De elopmen
Du ing ib ous plaque de elopmen , a he oma plaques unde go a ansi ion om he
a y s eak o in imal g owing, a s ep cha ac e ized by he p esence o a cell- ee and lipid-
ich a ea known as he nec o ic co e (Figu e 3). To s abilize he plaque, he nec o ic co e
is co e ed by ibe s, hus de eloping a ib ous cap. The nec o ic co e and he ib ous cap
cons i u e he hallma k o ad anced a he oscle osis [
171
], and a he oma plaque eg ession
is unlikely o happen in his s age [172,173].
Figu e 3.
Schema ic ep esen a ion o a he oma plaque o ma ion om a heal hy a e y o plaque
up u e unde lying he mos impo an e en s ha con ibu e o i s de elopmen in each s age.
4.1. Fib ous Cap
The ib ous cap is a subendo helial ba ie be ween he lumen o he essel and he
a he oscle o ic nec o ic co e consis ing o VSMCs ha ha e mig a ed o he luminal side
o he a e y and ex acellula ma ix (ECM) de i ed om VSMCs [
174
,
175
]. The ole o
he ib ous cap is o se e as a s uc u al suppo o a oid he exposu e o p o h ombo ic
ma e ial o he co e ha o he wise would igge h ombosis [174].
A he physiological si ua ion, di e en ia ed VSMCs o he unica media show a
con ac ile pheno ype ha egula es he blood essel diame e and blood low [
176
–
178
].
Howe e , in esponse o inju y, VSMCs swi ch hei pheno ype o he syn he ic one in which
mig a o y and p oli e a ion ac i i ies p e ail [
179
,
180
]. Fo ha pu pose, neighbo ing cells
ac i a e he healing p ocess by p oducing se e al g ow h ac o s, which include epide mal
g ow h ac o , ib oblas g ow h ac o , insulin-like g ow h ac o , pla ele -de i ed g ow h
ac o (PDGF), ans o ming g ow h ac o -
β
(TGF-
β
), and ascula endo helial g ow h
ac o (VEGF) [
179
]. In a he oscle osis, in esponse o he g ow h ac o s p oduced by
oam cells (VSMC- o mac ophage-de i ed) o ECs o he in ima, VSMCs om he unica
media mig a e o he in ima [
175
,
179
,
181
–
183
]. Mo eo e , IL-1 p oduced by mac ophages
enhances he endogenous p oduc ion o PDGF by VSMC, and, once in he in ima, i au-
oc inically leads o hei p oli e a ion [
184
,
185
]. In addi ion o mig a ion and subsequen
In . J. Mol. Sci. 2022,23, 3346 16 o 38
endo helium [
310
]. In pa icula , VSMCs can deli e miR-143/145 o ECs ia memb ane
nano ubes o unneling nano ubes [
310
]. The ans e o miR-143/145 om VSMCs o
ECs is s imula ed by TGF-βsec e ed by ECs. VSMC-de i ed miR-143/145 diminishes he
angiogenic po en ial o he ECs by ep essing hexokinase II and in eg in β8 [310].
On he o he hand, miR-126 ac s as an in e cellula messenge mainly eleased by ECs
and in e nalized p ima ily by monocy es and VSMCs [
311
]. MiR-126 plays a c i ical ole in
modula ing ascula de elopmen and homeos asis, a ge ing speci ic mRNAs, including
he Sp ou y- ela ed p o ein 1 (SPRED-1), CXCL12, SDF-1, and phosphoinosi ol-3 kinase
egula o y subuni 2 (PIK3R2) [
312
–
317
]. MiR-126 has also been ela ed o he endo helial
dys unc ion associa ed wi h he de elopmen o diabe es and i s complica ions [318].
7.2. lncRNAs
The p og ess achie ed by nex -gene a ion sequencing echnologies has e ealed an
inc eased numbe o lncRNAs associa ed wi h he pa hogenesis o a he oscle osis [
319
].
Se e al lncRNAs iden i ied in plaque issues play a p o ec i e ole in ascula disease.
lncRNA MeXis (Mac ophage-exp essed LXR-induced sequence) is in ol ed in choles e ol
anspo . Animal models lacking MeXis showed an inc eased a he oscle o ic load and a
dec eased exp ession o he a he op o ec i e p o ein ABCA1 in a he oma plaques [
320
].
Reduced exp ession o lncRNA MALAT1 (me as asis-associa ed lung adenoca cinoma an-
sc ip 1) was also ound o be associa ed wi h he de elopmen o a he oma plaques [
321
].
The knockdown o MALAT1 p omo es lipid up ake in oam cells by inducing he an-
sc ip ion o sca enge ecep o CD36 [
322
]. Mo eo e , lncRNA CHROME (choles e ol
homeos asis egula o o miRNA exp ession) p o ec s agains a he oscle osis p omo ing
choles e ol e lux by inhibi ing miRNAs, such as miR-33 [
323
,
324
]. Howe e , ew lncRNA
ha e shown a he o-p o ec i e e ec s by inhibi ing apop osis and senescence. In pa icu-
la , lncRNA CERNA1 p omo es plaque s abiliza ion by inhibi ing cellula apop osis ia
inducing API5 exp ession [
325
], and lncRNA SNHG12 in pig and human a he oma plaques
inhibi s DNA damage and senescence [
326
]. Human ca o id a he oscle o ic plaques show
dec eased le els o lncRNA NEXN-AS1 and lncRNA MANTIS [
327
,
328
]. NEXN-AS1 up-
egula es he exp ession o NEXN, a gene ha exe s a he op o ec i e e ec s in VSMCs
and ECs [
327
]. Fu he mo e, one lncRNA, called SENCR (smoo h muscle and EC-en iched
mig a ion/di e en ia ion-associa ed long noncoding RNA), plays a ole in a he oscle osis
de elopmen by p o ec ing he endo helial laye [
329
]. Hence, Boulbe da e al. [
330
] ound
al e ed le els o lncRNA SENCR in ascula issue. Mo eo e , he newly iden i ied lncRNA
RP11-714G18.1 is also down egula ed in a he oma plaques. This lncRNA inhibi s VSMC
and EC mig a ion by down egula ing he exp ession o MMP1, inhibi ing a he oscle osis
p og ession. In addi ion, RP11-714G18.1 inhibi s he adhesion o monocy es o ECs [331].
A ecen s udy highligh ed he ole o lncRNA SMILR in a he oscle osis and showed
ha i s exp ession is signi ican ly highe in uns able plaques han in s able plaques and
inc eases VSMC p oli e a ion by egula ing he exp ession o he p oximal gene HAS2 [
332
].
Mo eo e , lncRNA SMILR binds di ec ly o he mRNA o he mi o ic p o ein CENPF (cen-
ome e p o ein F) d i ing he p oli e a ion o smoo h muscle cells [
332
]. The abe an
p oli e a ion and mig a ion o VSMCs a e c i ical ac o s in a he oscle o ic plaque o ma-
ion, and se e al molecula mechanisms ha in ol e lncRNAs con ol hese p ocesses.
Among he lncRNAs ha supp ess VSMC mig a ion, lncRNA RP11-714G18.1 ac s by di-
ec ly a ge ing LDL- ela ed ecep o 2 binding p o ein (LRP2BP) in a he oscle osis [
331
].
Ve y ecen ly, i has been ound ha lncRNA ZNF800, which is highly exp essed in human
a he oscle o ic plaque issues and p edominan ly in VSMCs, supp esses VSMC p oli e -
a ion and mig a ion h ough he AKT/mTOR/HIF-1
α
signaling pa hway by ac i a ing
PTEN [
333
]. Ano he s udy demons a ed ha lncRNA RNCR3 exp ession is signi ican ly
highe in a he oscle o ic lesions, leading o educed VSMC p oli e a ion and mig a ion
ia he RNCR3/K uppel-like ac o 2/miR-185-5p egula o y ne wo k [
334
]. Fu he mo e,
lncRNA RP11-714G18.1 impai s VSMC mig a ion in a he oscle osis h ough he LRP2BP-
media ed down egula ion o MMP1 [
331
]. The exp ession o lncRNA p21 is also educed

In . J. Mol. Sci. 2022,23, 3346 17 o 38
in a he oscle o ic plaques, and i ep esses VSMC p oli e a ion and a he oscle osis by
enhancing TP53 ac i i y, hus playing an a he op o ec i e ole in a he oscle osis [335].
Simila ly, lncRNA CCL2 is up egula ed in uns able a he oscle o ic plaques compa ed
o s able a he oscle o ic plaques. Mo eo e , lncRNA CCL2 modi ies he mRNA le els
o he p o-in lamma o y chemokine CCL2 (o MCP-1) by in e ac ing wi h RNA binding
p o eins (HNRNPU and IGF2BP2) [
336
]. Recen ly, lncRNA GAS5
(g ow h a es -speci ic 5)
has ecei ed a en ion as a po en ial bioma ke o a he oscle osis [
337
]. Le els o GAS5
we e up egula ed in a he oscle o ic plaques, and GAS5 binds and supp esses he mi-
c oRNA miR-221, inc easing he p oduc ion o MMPs and p o-in lamma o y molecules
wi hin he a he oscle o ic plaque [
338
]. A slan e al. [
321
] ha e iden i ied he up egula-
ion o lncRNA MIAT (myoca dial in a c ion-associa ed ansc ip ) in a he oma plaques.
MIAT inc eases VSMC p oli e a ion by binding and supp essing miR-181b [
339
]. An-
o he lncRNA ha displayed e ec s on VSMC p oli e a ion and mig a ion is BANCR
(BRAF- egula ed lncRNA 1) [340].
Finally, lncRNA ANRIL (an isense non-coding RNA in
he INK4 locus) is also a c ucial molecule in a he ogenesis, as i a ec s se e al cell ypes in
he a he oscle o ic plaque, whe e i is up egula ed and is di ec ly co ela ed wi h a he oscle-
osis se e i y [
341
,
342
]. Recen ly, ci cula o ms o ANRIL (ci cANRIL), comp ising di e en
exons and opposed o he linea o m, ha e been iden i ied. Con e sely, ci cANRIL is
in e sely co ela ed wi h a he oscle osis isk [
343
]. Ci cANRIL has been ound in ascu-
la issue, smoo h muscle cells, and mac ophages, whe e i exhibi s an a he o-p o ec ion
unc ion [342].
In summa y, ecen indings sugges ha lncRNA plays a c ucial ole in he de elop-
men o a he oscle o ic plaque (Table 4). Howe e , o mos o hem, he speci ic mode
o ac ion is no comple ely unde s ood, and u he esea ch is needed o unde s and he
complex ole o lncRNA in a he oscle osis.
Table 4. Role o lncRNA in a he oscle osis.
A he o-P o ec i e P o-A he ogenic
MeXis [304]
MALAT1 [321,322]
CERNA1 [325]
SNHG12 [326]
NEXN-AS1 [327]
MANTIS [328]
SENCR [329]
RP11-714G18.1 [331]
CHROME [323,324]
ci cANRIL [342]
SMILR [332]
CCL2 [336]
GAS5 [337,338]
MIAT [321,339]
BANCR [340]
ANRIL [341,342]
8. Mic obio a
The human body hos s many bac e ia species (mic obio a) ha ha e co-e ol ed wi h
humans, and hey ha e gene a ed a symbio ic ela ionship ha mu ually bene i each o he .
Mic obio a is able o posi i ely a ec human physiology h ough he syn hesis o di e en
me aboli es o he aining o he immune sys em; howe e , i has also been associa ed wi h
he de elopmen o di e en diseases, such as a he oscle osis o ca dio ascula disease
(CVD) [344,345].
The p esence o mic oo ganisms in he a he oma plaque is well es ablished, and some
s udies ha e shown ha he abundance o ce ain phyla could co ela e wi h plaque s abili y
and o e all in lamma ion [
346
,
347
]. Fo ins ance, bac e ial DNA om pa hogenic amilies,
such as Helicobac e aceae o Neisse iaceae, has been shown o be mo e abundan in plaques
o symp oma ic pa ien s [
348
,
349
]. Ne e heless, hese esul s need o be co obo a ed in
la ge s udies.
Gu mic obio a also con ibu es o he de elopmen o a he oscle osis and CVD. The
gu hos s he la ges mic obial popula ion in humans and is able o egula e many biologi-
In . J. Mol. Sci. 2022,23, 3346 18 o 38
cal unc ions, such as ene gy s o age, he abso p ion and p ocessing o nu ien s, o he
ma u a ion o he immune sys em [
350
,
351
]. Howe e , when gu mic obial homeos asis
is dis up ed ( e e ed o as dysbiosis) owa d unde ep esen ed colonies, i can induce
he de elopmen o di e en diseases, such as cance , ype 2 diabe es, obesi y, CVD, and
a he oscle osis [
346
,
352
,
353
]. In addi ion, gu dysbiosis inc eases in es inal pe meabil-
i y, educing he exp ession o igh junc ion p o eins and allowing he ansloca ion o
lipopolysaccha ides ha induce low-g ade in lamma ion ia Toll-like ecep o s [
354
]. On
he o he hand, se e al me aboli es p oduced by he gu mic obio a can modula e sys emic
in lamma ion and con ibu e o p e en a he oscle osis de elopmen . The mos s udied
one is ime hylamine-N-oxide (TMAO) [
355
], he oxidized o m o ime hylamine (TMA).
TMA is syn hesized by gu mic obio a a e me abolizing die choline and ca ni ine. I
is hen ans e ed o he bloods eam and oxidized o TMAO in he li e h ough la in
mono-oxigenase [
356
]. TMAO inc eases ascula wall in lamma o y esponses and sup-
p esses e e se choles e ol anspo a o ing choles e ol accumula ion in he in ima [
357
].
Mo eo e , APOE
−/−
mice ed wi h a choline- ich die showed inc eased TMAO le els and
a he oma plaque de elopmen , a p ocess ha was e e sed by an ibio ic in e en ion [
358
].
Indi ec in ec ions in dis an a eas om a he oma plaques also con ibu e o i s de-
elopmen and des abiliza ion. Indeed, in ecen yea s, many s udies ha e co ela ed
he incidence o a he oscle o ic ca dio ascula disease (ACV) wi h bac e ial in ec ions.
Epidemiological s udies suppo he idea o a causa i e associa ion be ween pe iodon-
al disease o chlamydia in ec ions and CVD [
359
]. A la ge s udy ha included almos
12,000 pa icipan s demons a ed ha poo o al hygiene is associa ed wi h an inc eased
a e o CVD and inc eased lowe -g ade in lamma ion [
360
]. Mo eo e , a small s udy wi h
92 pa icipan s showed ha some bac e ia phyla we e mo e abundan in he o al ca i y o
pa ien s wi h symp oma ic a he oscle osis han in con ol pa ien s, indica ing a possible
associa ion be ween o al bac e ia and a he oma plaque de elopmen [
361
]. Ne e heless,
he di ec associa ion o bac e ia in he o al ca i y and ACV is s ill con o e sial [362].
9. Sex as an Impo an Risk Fac o in A he oscle osis
Se e al modi iable and non-modi iable a he oscle o ic isk ac o s ha e been well
desc ibed. Among hem, unheal hy die , physical inac i i y, dyslipidemia, hype glycemia,
high blood p essu e, obesi y, sex, and age [
363
–
366
]. He e, he impac o sex on a he oscle-
osis will be co e ed in de ail.
The pa hophysiology o a he oscle osis shows di e en pa e ns be ween women
and men due o inhe en biological and social di e ences (e.g., Younis, N.). In 1948, he
US Public Heal h Se ice ini ia ed he F amingham s udy, which indica ed ha sexual
dimo phism in majo modi iable isk ac o s, including ciga e e smoking, dyslipidemia,
hype ension, and diabe es melli us, could be esponsible o he obse ed di e ences in
a he oscle osis de elopmen and/o complica ions [
367
]. Since hen, la ge da ase s ha e
shown ha he impac o hese isk ac o s on he associa ed isk o myoca dial in a c ion
(MI) is highe in women compa ed o men, wi h odds a ios o 1.3, 1.5, and 1.6, o
smoking, hype ension, and diabe es melli us, espec i ely [
368
,
369
]. In addi ion, mode n
epidemiological da a show ha younge women ha e a dec eased isk o de elop CVD
and lowe a es o MI ela i e o men [
370
,
371
]. Howe e , he obse ed ca diop o ec i e
e ec in women is los be ween he age o 60 and 79 yea s, and CVD isk in women
su passes ha in men by he age o 80 yea s [
371
]. None heless, his pa e n o disease
onse is no ecapi ula ed in s oke, which shows a g ea e p e alence in women un il he
se en h decade o li e and a g ea e p obabili y o ecu en s oke wi hin he i s 5 yea s
a e s oke compa ed o men [
372
]. Addi ionally, co ona y a e y disease (CAD) is o en
unde diagnosed and iewed as a leading cause o emale mo ali y. In Eu ope, CVDs
accoun o 43% o dea hs in men and 55% in women [
373
]. When analyzing he di e en
componen s o CVDs, co ona y hea disease (CHD) ep esen s 21% o dea hs in men and
23% in women, whe eas, as indica ed abo e, s oke is a mo e equen cause o dea h in
women han in men (18 and 11%, espec i ely), as well as he o he CVDs (15% in women
In . J. Mol. Sci. 2022,23, 3346 19 o 38
and 11% in men). These demog aphic s a is ics e idence sex di e ences in CVD isk and
highligh he need o ake in o conside a ion sex as an impo an a iable o be included
om animal models h ough clinical ials [372].
Al hough g ea e o s ha e been made o unde s and molecula mechanisms and
disco e no el d ug a ge s o a he oscle osis, da a examining sex di e ences a e s ill
ela i ely limi ed. A obus s udy, in which 771 p eclinical a icles on a he oscle osis and
o he ascula diseases we e analyzed, showed ha he sex o animals is no epo ed
in he 18.8% o hem. When he sex was speci ied, 55.4% o he s udies we e pe o med
on males, 20.4% we e pe o med on emales, and less han 25% s udied bo h males and
emales [
374
]. The p opo ion o s udies including bo h sexes was e y simila (21–28%) in
ecen ly published a icles [
375
,
376
]. Mo eo e , ewe han hal o he s udies including
bo h sexes di ec ly compa e males and emales wi h he app op ia e s a is ical analysis
o conside sex as an independen a iable o he in e ac ion o sex wi h a ea men o
geno ype [
374
–
376
]. Di e en pa e ns in CVD incidence be ween women and men a e
shown in Figu e 4.
Figu e 4. Di e en pa e ns in CVD incidence be ween women and men.
9.1. Impac o Plaque Size and Mo phology be ween Sexes
F equen ly, exe ional ischemia (i.e., angina and claudica ion) occu s when an indi id-
ual plaque enla ges su icien ly o impai blood low o mee issue demand (usually >70%
s enosis). On he o he hand, plaque up u e leads mos o he mo bidi y and mo ali y
e en s om a he oscle osis, such as MI, s oke, disabling pe iphe al a e y disease, and
e en ually dea h. Non-in asi e imaging has shown ha men de elop plaques ea lie
and ha e a g ea e plaque bu den han women, e en a e accoun ing o di e ences in
isk ac o s. In addi ion, pos -mo em pa hological s udies ha e shown ha plaques wi h
30–40% s enosis a e mo e likely o up u e, leading o ascula occlusion and dea h [
377
].
These s udies sugges ha an o e all plaque bu den, a plaque in lamma o y s a e, and an
uns able plaque mo phology con ibu e o acu e MI and s oke isk, in ag eemen wi h he
g ea e incidence o ischemic e en s in males, al hough his ela ionship changes la e in
In . J. Mol. Sci. 2022,23, 3346 20 o 38
ime [
378
–
380
]. Addi ionally, i has been shown ha women do no p esen as much o an
a he oscle o ic plaque bu den as men and ha e ewe high- isk plaque ea u es [381–383].
Signi ican ly mo e a he oscle o ic and calci ied plaques, highe a es o CAD, and majo
ad e se ca diac e en s o e 5.6 yea s o ollow-up ha e been obse ed in men compa ed
wi h women [
380
]. Mo eo e , he c oss-sec ional REFINE-Reykja ik s udy, which included
21,132 pa ien s, showed ha 50% o women had no mal compu ed omog aphy scans
compa ed wi h 31% o men [378].
New imaging echniques allow one o assess indi idual a he oscle o ic plaque ea-
u es ha a e associa ed wi h ad e se e en s. In a ascula ul asound, which p o ides
in o ma ion abou bo h he deg ee o s enosis and he ex en o nec o ic co e in he plaque,
has shown ha women su e ing om acu e co ona y synd ome p esen a simila numbe
o culp i s compa ed o men [
379
]. Ne e heless, despi e a highe mean age and mul iple
como bidi ies, women p esen ewe non-culp i lesions, ewe in ol ed co ona y a e -
ies wi h lesions, a lowe equency o plaque up u e, and a smalle o al nec o ic co e
olume [381,384].
9.2. Clinical Implica ions
The impo ance o unde s anding age and gende di e ences in culp i plaque com-
posi ion is c ucial o choose mo e app op ia e pha macological and in e en ional he a-
pies [
385
]. The signi ican ly highe p e alence o hin-cap ib oa he oma in elde ly women
pa ien s compa ed o men shows he impo ance o in ensi e lipid-lowe ing he apy o
women [
386
]. Howe e , ecen s udies ound ha women we e less likely o be eligible
o s a in adminis a ion han men, due o women being o e ed s a ins a a lowe a e
by hei ca egi e s [
387
–
389
]. Su icien in ensi y and du a ion o lipid-lowe ing he apy,
including s a ins, should be p o ided o women as ha p o ided o men [
386
]. Wi h he
imbalance o choles e ol me abolism being a key ac o in he p og ession o a he oscle osis
by inc easing age in women, eze imibe in combina ion wi h s a ins migh also be e ec i e
o s abilize co ona y plaque in women [390,391].
In con as o he ea men and p e en ion o ulne able plaque, he he apeu ic s a -
egy o co ona y calci ica ion may be mo e complex and challenging. Fo he in e en ional
ea men o culp i lesions wi h la ge calci ica ion, in aco ona y imaging echniques may
p o ide sa e p ocedu es and be e clinical ou comes [
392
,
393
]. None heless, lesions wi h
la ge plaques also equi e he use o a debulking de ice, and a subsequen wide s en
a ea is also equi ed o calci ica ion [
394
]. In addi ion, li es yle modi ica ion may be mo e
impo an in women han in men ega ding he isk educ ion o a he oscle o ic change
in plaque componen s and subsequen disease onse [
395
,
396
], as hey a e conside ed
modi iable ac o s.
10. Ciga e e-Smoking-Induced A he oscle osis
Ciga e e smoking is a powe ul independen isk ac o o a he oscle osis and
ACV e en s, since chemical cons i uen s o smoke ha e high oxidan and in lamma-
o y capaci ies ha can di ec ly induce endo helial damage and po en ia e in lamma o y
esponse [397–401].
Clinical e idence has shown a di ec p opo ional dose-dependen
associa ion o smoking exposu e wi h he p esence o ex ensi e and calci ied a he oscle o ic
plaques, and smoking cessa ion a any age is one o he mos impo an heal h in e en ions
o educing isks o ACV, cance , and mo ali y [
402
]. Smoking cessa ion has been asso-
cia ed wi h less p og ession o ca o id plaque, bu no wi h in ima media- hickness [
403
].
The e ec s o smoking cessa ion on ca o id a he oscle osis we e ela ed o he deg ee o
abs inence and pe sis ed a e adjus ing o baseline smoking hea iness and ACV isk
ac o s [403].
In . J. Mol. Sci. 2022,23, 3346 21 o 38
Molecula Mechanisms Unde lying Clinical Smoking-Induced A he oscle osis
I has been shown ha single smoking compounds (e.g., nico ine, ca bonyl compounds,
ac olein, and me hyl inyl ke one) and/o hei combined ac ion can a ec each s age o
he a he oscle o ic p ocess [401].
Exposi ion o smoke can p omo e oxida i e s ess, which cons i u es one o he main
mechanisms unde lying endo helial inju y. As men ioned abo e, oxida i e s ess in luences
he ac i i y o nume ous enzymes (e.g., eNOS and NADPH–oxidases) [
404
] and leads o
i e e sible modi ica ion o di e en p o eins, he eby deeply al e ing in acellula signaling
pa hways. Smoke is able o inc ease LDL le els h ough me abolic al e a ions and he
induc ion o LDL oxida ion due o he di ec oxidan capaci y o smoke componen s [
401
].
Smoke exposi ion also leads o NF-
κ
B ac i a ion in ECs, inc easing he exp ession o
adhesion molecules on he plasma memb ane [
405
] and he up egula ion o in lamma o y
genes, including IL-1 and COX-2 [
406
]. Fu he mo e, nico ine igge s he sec e ion o
p o-in lamma o y adipokines om he pe i ascula adipose issue [407].
Mo eo e , smoking induces he p oli e a ion and mig a ion o VSMCs and he swi ch
om con ac ile o sec e o y pheno ype by inc easing he exp ession o IFN-
β
and
PDGF [305,408].
Consequen ly, VSMCs a e able o elease p o-in lamma o y ac o s and
ex acellula ma ix componen s.
A he oscle o ic plaques o smoke s a e cha ac e ized by a p edominance o he lipid
co e, and he ib o ic cap is hinne han in non-smoke s [
409
]. This con igu a ion is pa ly
due o augmen ed MMP ac i i y in he plaque o smoke s [
410
,
411
]. Smoking also igge s
he in il a ion and ac i a ion o mac ophages inside he lesion, as well as hei con e sion
in oam cells, con ibu ing o he g ow h o he lipid co e. Smoking is also essen ial in
he p ocess o pla ele ac i a ion and adhesion o endo helium [
412
]. In addi ion o hese
e ec s, smoking can cause an inc ease in blood p essu e, a de e minan o plaque damage
and ins abili y.
Se e al mic oRNA pa hways ha a e in ol ed in he de elopmen o a he oscle osis
a e also egula ed by ciga e e-smoke exposu e [
413
,
414
]. I has been shown ha exposu e o
high-dose ciga e e smoke leads o he up egula ion o miRNA-155 and miRNA-21, which
a ge PPAR-
α
. The down egula ion o PPAR-
α
leads o he up egula ion o VCAM-1,
ICAM-1, and MCP1 h ough he ac i a ion o ansc ip ion ac o AP-1 [
415
,
416
]. VCAM-1
and ICAM-1 media e he i m adhesion o leukocy es o he ECs and play a c i ical ole in
subsequen leukocy e ansmig a ion, leading o a he oscle osis [
417
,
418
], whe eas MCP-1
egula es he mig a ion and in il a ion o monocy es/mac ophages [419].
In addi ion, he up egula ion o miR-155 and miR-21 modula es he EGFR/ERK/p38
MAPK and he PI3K/Ak /eNOS pa hways in ECs, espec i ely [420,421].
11. Conclusions
Du ing he las ew yea s, we a e wi nessing an inc eased bu den o a he oscle o ic
disease ha con ibu es o CVD isk, which is becoming a global epidemic. The s udy o
cellula and molecula biology mechanisms o a he oscle osis has p o ided ema kable
insigh s in o he p ocesses ha lead o a he oma de elopmen and he clinical mani es a-
ions o his disease. Knowledge and con inued esea ch abou he unc ions o non-coding
RNAs in plaque de elopmen ha e imp o ed, showing ha miRNAs and lncRNAs al e
he ansc ip ion o genes implica ed in a he oscle osis. In addi ion, mic obio a ha e been
linked o he de elopmen o a he oscle osis by iden i ying mic obial ecosys ems esiding
in di e en habi a s o he human body ha con ibu e o me abolic and ca dio ascula
diso de s. The ole o mic obio a in a he oscle osis de elopmen is suppo ed by inc easing
mechanis ic e idence; howe e , u he s udies a e needed o unde s and he con ibu-
ion o mic obio a o a he oscle osis. Finally, he impo ance o analyzing sex-speci ic
di e ences as isk ac o s associa ed wi h a he oscle osis is impo an o indi idualized
isk-managemen s a egies o p e en he de elopmen and p og ession o a he oscle osis.

In . J. Mol. Sci. 2022,23, 3346 22 o 38
The p og ess in unde s anding he mechanisms ha lead o a he oscle osis de elop-
men will su ely p o ide he apies o add ess he unaccep able bu den o pe sis en isk
and will ul ima ely imp o e he diagnosis and p ognosis o he disease.
Au ho Con ibu ions:
Concep ualiza ion, S.J.-B., A.B.-V. and C.M.; w i ing—o iginal d a p epa a-
ion, S.J.-B., A.L.-S., U.G.-G., A.B.-V., J.R.O., I.A., K.V. and C.M.; w i ing— e iew and edi ing, S.J.-B.,
A.B.-V. and C.M. All au ho s ha e ead and ag eed o he published e sion o he manusc ip .
Funding:
This wo k was suppo ed by he Basque Go e nmen (G upos Consolidados IT-1264-
19). A.B.-V. was suppo ed by P og ama de especialización de Pe sonal In es igado Doc o en la
UPV/EHU (2019) 2019/2020; U.G-G. was suppo ed by Ma ga i a Salas G an ; and S.J. and A.L-S
we e suppo ed by a g an PIF (2017–2018) and PIF (2019–2020) Gobie no Vasco, espec i ely.
Ins i u ional Re iew Boa d S a emen : No applicable.
In o med Consen S a emen : No applicable.
Con lic s o In e es : The au ho s decla e ha he e is no con lic o in e es .
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