Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3616_Библиотеки_им_академика_М_И_Перельмана
.pdf
Part I
https://t.me/med1917
Overview
Chapter 1
https://t.me/med1917
Aging Aorta—Cellular Mechanisms
Florentina Radu-Ionita
1,2
, Ion C. Ţintoiu
Romi Bolohan3, Constantin Silvestru3, Mircea Ifrim7, Iancu Mocanu3, Dan Riga
Sorin Riga
1
“Titu Maiorescu” University of Bucharest, Bucharest, Romania; 2“Carol Davila” Emergency Central Military Hospital, Bucharest, Romania; 3“Vasile
Candea” Army's Center for Cardiovascular Diseases, Bucharest, Romania; 4“Carol Davila” University of Medicine and Pharmacy, Bucharest,
Romania; 5“Prof. Dr. C. C. Iliescu” Emergency Institute of Cardiovascular Diseases, Bucharest, Romania; 6Hospital SANADOR, Bucharest, Romania;
7
Romanian Academy of Medicine, Bucharest, Romania; 8Academy of Romanian Scientists, Bucharest, Romania; 9ARS Medical Sciences Section,
Bucharest, Romania;
Romania; 12Romanian Medical Sciences Academy, Bucharest, Romania; 13Center Hospitalier Coutances, Coutances, France
A man is as old as his arteries.
10,11,12
, Dragos Savoiu3, Ambrose Kibos
10
European Academy of Sciences and Arts, Bucharest, Romania; 11Clinical Psychiatric Hospital “Prof. Dr. Obregia”, Bucharest,
1,3
, Andrei Rosu
13
3,4
, Ecaterina Bontas5, Daniel Cochior
8,9,10,11
, Vasile Murgu3,
Thomas Sydenham (1624–1689)
1,6
,
Chapter Outline
Aging and Stiffness Aorta 3
Intima–Endothelial Senescence 4
Intima and Media—Apoptosis 5
Intima–Extracellular Matrix and MMPs Roles 6
Media–VSMCs 7
Media–Elastin/Collagen Ratio 8
Media Inflammation 9
Telomere Length—A Biomarker of Aorta Aging 9
Atherogenesis 13
Conclusions 14
References 16
Further Reading 23
AGING AND STIFFNESS AORTA
Initially, increasing data support that arterial stiffness is an excellent and obvious biomarker for cardiovascular disease (CVD)
and its related risks [1–14]. With respect to their basic architecture, arteries are usually described as cross-sectional arrangements of cells and extracellular matrix (ECM). As a standard, ECM within the media comprises lamellae of elastic material,
layers of vascular smooth muscle cells (VSMCs), and collagen fibers [15]. Collagen is two times more stiffer than elastin
and VSMC [16] but predominates in peripheral arteries. As a side note, structures such as VSMCs from young arteries of the
arterial wall give elasticity through the protein components such as ECM, elastin, fibrillin, collagen, glycoproteins, and proteoglycans [17]. As a consequence, there is a progressive increase in vessel stiffness from the proximal to distal arterial compartments. With advancing age, the human aorta dilates and becomes stiffer with physiological pressures [18–22]. Specifically,
the dominant element of arterial aging is the stiffening and dilation of the proximal aorta, known as “senile arteriosclerosis”
as already explained by Osler [23]. In fact, elastic arteries have two alterations with age [24]: (1) dilation and (2) stiffening are
the most evident in the proximal aorta with its major branches [24–27]. As previously reported, it is worthy to note that pure
arterial aging was observed frequently in Chinese populations without atherosclerosis [25,26].
In summary, there are multiple cellular and intracellular mechanisms that further determine the loss of elasticity of the
aorta. Of these, the most significant mechanisms mentioned earlier are (1) apoptosis of tunica media; (2) migration, proliferation, and infiltration by VSMCs of the subendothelial layer; (3) changes with proliferation of ECM in intima (tunica
interna); (4) infiltration with inflammatory cells; (5) fragmentation of elastin and collagen tissue initially replaced in tunica
media and then expanding in the underlying and overlying layers; (6) telomere shortening, decrease of the line in stem cell
number and their function, atherogenesis, calcification, and so on. Altogether these mechanisms and others are implied in
the stiffness of the aorta wall. The information is presented in Table 1.1.
New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation. http://dx.doi.org/10.1016/B978-0-12-809979-7.00001-8
Copyright © 2018 Elsevier Inc. All rights reserved.
3
4 PART | I Overview
(A) (B) (C)
https://t.me/med1917
TABLE 1.1 Mechanisms of Changes in Aging Aorta Wall
Intima Media Adventitia
l
Endothelial apoptosis [3,28–30]
l
Endothelial senescence [3,28–30]
l
Deposition VSMCs infiltrate into the
subendothelial space [3,28–30]
l
ECM production [31,32]
l
Collagen propagation [30]
l
↑VSMC [30]
l
Proliferation [30,33,34]
l
Migration and Invasion [3,28–30]
l
Apoptosis [3,28–30]
l
↑MMPs, ↑ICAM [3,28–30]
l
Collagen propagation [30]
l
Increased stiffness [3,28,35]
l
Elastin fragmentation [31,32]
l
Calcification [36]
l
↑Inflammatory cells [31,32]
l
Collagen/elastin ratio increased (↓elastin,
l
(Myo)fibroblasts [37–39]
l
Calcification [36]
l
AGE [3,28–30]
l
Amyloidosis [40]
l
Modified ECM [3,28–30]
↑collagen) [30]
Others
l
Telomere shortening and cellular senescence [41,42]
l
Decline in stem cell number and function [43]
l
Atherogenesis [44]
AGEs, advanced glycation end-products; Ang II, angiotensin II; ↓decrease; ECM, extracellular matrix; ↑increase; ICAM, intracellular adhesion molecule;
MMPs, matrix metalloproteinases; VSMC, vascular smooth muscle cell.
(D) (E) (F)
FIGURE 1.1 Fibrosis of the adventitia in Hutchinson–Gilford progeria syndrome (HGPS). Hematoxylin and eosin (H&E) staining of selected tissues
from patients HG001 (A) and HG120 (B and C). (A) Aorta with thickened adventitia (arrow). (B) Mid-right coronary characterized by an enlarged and
highly fibrotic adventitia (arrow). The media is markedly thinned in the area with adventitial fibrosis. (C) High-power image of the adventitia (arrow)
shown in (B). (D) A 16-year-old non-HGPS aorta with nondiseased adventitia (arrow). (E) A 16-year-old non-HGPS left anterior descending (LAD). (F)
A 93-year-old LAD with advanced atherosclerosis. Arrowhead points to the adventitia. ad indicates adventitia; m, media. (Scale bars: A, C, and D, 50 μm;
B, E, and F, 500 μm.) From Olive M, Harten I, Mitchell R, Beers JK, Djabali, K, Cao, K, Erdos, MR, Blair, C, Funke, B, Smoot, L, Gerhard-Herman, M,
Machan, JT, Kutys, R, Virmani, R, Collins, FS, Wight, TN, Nabel, EG, Gordon, LB. Cardiovascular pathology in Hutchinson-Gilford progeria: correlation
with the vascular pathology of aging. Arterioscler Thromb Vasc Biol November 2010;30(11):2301–09 with permission.
INTIMA–ENDOTHELIAL SENESCENCE
Senescence should not be confounded with the death of senescent cells that can progress on long periods of time [45]. The first
description of halting of cell division was studied by Hayflick and Moorhead in normal human fibroblasts culture [46]. In particular, endothelial senescence is an irreversible increase unresponsive to numerous stressors [47,48]. In this way, Olive et al. (2010)
evaluated genetically diagnosed children with Hutchinson–Gilford progeria syndrome, which revealed extremely increased CVD,
with important mortality from myocardial infarction or stroke for the age group between 7 and 20 years (Fig. 1.1) [49].
Aging Aorta—Cellular Mechanisms Chapter | 1 5
https://t.me/med1917
Basically, cellular senescence is the hallmark of an aging organism characterized by irremediable development of blockage cell morphology, growth of DNA oxidative stress, decreasing of telomere length, amplified representation of senescence-related β-galactosidase (SA-β-gal), and a greater elevation of cyclin-dependent kinase inhibitors affiliated to tumor
suppressor pathways, specifically (p16/p19/p21) [50–53]. Another characteristic of “cellular senescence” is the Senescence
Associated Secretory Phenotype (SASP) with the secretion of proinflammatory cytokines that function together within
inflammation process [54]. Furthermore, one more finding of senescence is related to the epigenome [55]. As a result, DNA
methylation is decreasing during senescence with the disequilibrium of chromosomal activity. Aneuploidy or polyploidy is
often seen in aging cells being associated with the decay of DNA restoration [56].
Senescent endothelial phenotypes are described by increasing inflammatory markers such as inflammatory
adhesion molecules vascular cell adhesion molecule 1 (VCAM1) and intracellular adhesion molecule 1 (ICAM1),
decreased nitric oxide (NO) formation with raised oxidative stress triggered by endothelial NO synthase (eNOS)
uncoupling, and raised expression of aging oxidative stress markers [47,57–61]. Consistent with a growing evidence,
eNOS uncoupling is a major process of oxidative stress associated with reduced NO bioavailability in endothelial
senescence, with vascular aging and age-related CVD [42,62,63]. Another important regulator of organism aging is
mTOR (mammalian target of rapamycin)/S6K1 [64,65], implicated in regulation of many cellular functions [64].
Essentially, senescent human endothelial cells exhibit raised amounts of VCAM1 and ICAM1 in comparison with
young cells (nonsenescent cells) [61].
As already described by evidence, microribonucleic acid (miRNA) especially miR-34a is correlated with endothelial
senescence by its increased expression in murine and humans with age [66–69]. For instance, increased miR-34a exists dur-
ing the culturing of endothelial and endothelial progenitor cells and may speed up the phenotype of senescence via “direct
downregulation of one of its target genes,” Sirtuin-1 (SIRT1) [67,69]. Therefore, it is important to underline that SIRT1 can
cancel out the processes of senescence mediated by VSMCs of atherogenesis and vascular calcification [70,71] (Fig. 1.2).
In conclusion, endothelial senescence is the main feature of vascular aging and supports the progress of atherosclerosis. As
well, reduced SIRT1 expression facilitates the occurrence of senescence in endothelial cells [74–78] and atherosclerosis [78].
INTIMA AND MEDIA—APOPTOSIS
All cells contain responsible structures for apoptosis. This process is the most significant in the vessel wall remodeling even
if at one moment it causes negative remodeling with a destructive role. In this regard, Mallat et al. (2000) described four
stages in the completion of apoptosis: (1) the initiation or signaling phase; (2) the control and the effectors phase; (3) the
DNA alterations phase; and (4) detection of apoptotic cells and removal of apoptotic bodies [79] (Fig. 1.3).
FIGURE 1.2 Sirtuin-6 (SIRT6) prevents endothelial senescence. Over-replication of endothelial cells (ECs) leads to decreased expression of SIRT6,
which in turn results in a proinflammatory phenotype, p21 upregulation, DNA damage, telomere dysfunction, cell cycle arrest, and impaired angiogenesis.
All are indications of EC senescence, but their cause–effect relationship is unknown [72]. From Shen J, Ma W, Liu Y. Deacetylase SIRT6 deaccelerates
endothelial senescence. Cardiovasc Res March 1, 2013;97(3):391–2 with permission.
6 PART | I Overview
1) Initiation Phase
FasL
TNF
2) Control and
Ef
https://t.me/med1917
Ionizing radiation, c-
myc, RB deficiency
p53
fector Phase
Bcl-2
Mitochondrion
Bcl-2
3) Structural
Alteration Phase
FIGURE 1.3 Schematic representation of main apoptotic pathways. Activation of caspase-8 (and subsequent activation of the caspase cascade) occurs
following ligation of death-signal-transmitting receptors. Caspase-9 activates cell disassembly in response to agents or insults that trigger the release of
cytochrome c from the mitochondria and is activated when complexed with deoxy-adenosine triphosphate, Apaf-1, and extramitochondrial cytochrome
c to form the multiprotein “apoptosome” ensemble. Caspase-8 and caspase-9 can activate caspase-3 by proteolytic cleavage, and caspase-3 amplifies
caspase-8 and caspase-9 signals into fully fledged commitment to disassembly, therefore, propagating the caspase cascade. Ligation of the death-signaltransmitting receptor TNFR (tumor necrosis factor receptor) may also generate signal transduction pathways leading to the activation of the nuclear transcription factor (NF)-κB and to the induction of cytoprotective genes. From Mallat Z, Tedgui A. Apoptosis in the vasculature: mechanisms and functional
importance. Br J Pharmacol July 2000;130(5):947–62 with permission.
Cyt C
Apaf-1
AIF
Fas
FADD
Caspase 8
Caspase 9
Caspase
cascade
Apoptosis
TNFR
TRADD
TRAF2
NF-κB
Cytoprotective
genes
In summary, the apoptosis of endothelial cells includes mechanisms for vascular injury and atherosclerosis [80–82]. Also,
endothelial cell apoptosis is carried out by the way of activation of caspases–cysteine protease family [83,84]. Further, nitric
oxide (NO) disturbes the apoptosis signal-transduction pathway [85,86]. It must be underlined that the apoptosis is inhibited
by restraining caspases by the way of S-nitrosylation of the basic cysteine remnants [84,87–89]. Regardless of this, it is already
acknowledged that the telomere damage has a major task in apoptosis and stress-caused senescence [90].
INTIMA–EXTRACELLULAR MATRIX AND MMPS ROLES
Stiffness of the large arteries is induced by several factors, mainly by the ECM proteins of the vessel wall named elastin and
collagen. Further, these structural proteins can be produced de novo in adults and are enzymatically degraded by elastases
and matrix metalloproteinases [91]. For instance, the elastin is a very stationary protein that permits blood vessels to return
to their shape after contracting or stretching [24,92]. VSMCs mostly produce the aorta elastin [93,94]. Also, it is important
to underline that the vessel tissue lacking fibrillin 1 microfibrils discharge MMPs, which further damage the vessel wall
with its dilatation. In fact, normal deterioration of the ECM has an onset during early adulthood for all mammalian species
[95]. The study of Fritze et al. (2010) [96] with multiphoton laser scanning microscopy of human aorta revealed a dramatic
decrease of these interlaminar elastic fibers with age and increase of spaces incompletely filled with proteoglycans within
the aortic media [97]. As a consequence, the aortic wall thickened [98].
MMPs represent a major function in the aortic disease [99] and are a large family of proteases [100,101]. They are
recognized as the main proteolytic enzyme group involved in the remodeling of ECM by modifying “cell–cell” and “cell–
matrix” interactions [102] (Fig. 1.4).
Various human MMPs have been documented [100]; they are separated into six groups: collagenases (MMP-1, -8, -13, and
-18), gelatinases (MMP-2 and -9), stromelysins (MMP-3, -10, -11, and -17), matrilysins (MMP-7 and -26), membrane-type
MMPs (MT-MMPs: MMP-14, -15, -16, -17, -24, and -25), and other MMPs (MMP-12, -19, -20, -21, -22, -23, -28, and -29)
[103]. After MMP synthesis, most of them are either secreted freely into the extracellular space or fixed to the surface of cell
membranes [104,105]. As expected, there is a precise control of MMP expression and function [103].
Conventionally, MMP-2 and MMP-9 have a significant task in vascular remodeling [106–108]. Increased human
MMP-2 and MMP-9 levels correlate with elastic laminae artery damage and aneurysm formation [109]. Moreover, MMP1, -2, -3, -8, and -9 are implicated in the increase in vascular remodeling by matrix damage with the splitting of intima from
the media [110]. Importantly, increased MMP2 activity coexists with VSMC apoptosis in the aorta, as well as bicuspid
Aging Aorta—Cellular Mechanisms Chapter | 1 7
Cadherin
https://t.me/med1917
Type IV collagen
FAK
α5β
Laminin
α1β
α2β
1
1
1
Collagen I
Fibronectin
MMPs
α
7β1
Stress
fibers
αvβ
3
Cleaved
cadherin
FIGURE 1.4 Matrix metalloprotein (MMP) influences the vascular smooth muscle cell (VSMC) migration. MMPs can remodel basement membrane
components, including laminin and type IV collagen, and help free cells to migrate. Loss of basement membranes promotes the phenotypic modulation
of VSMC. This leads to synthesis, among other things, of new integrin subunits and new matrix components that include glycoprotein ligands for these
integrins, for example, vitronectin, osteopontin, and tenascin. MMPs also fragment existing membrane components such as type I collagen and this can
create new integrin-binding sites. By acting through integrins and focal adhesion kinase (FAK), ECM components influence intracellular pathways that
regulate the cytoskeletal changes necessary for motion. MMPs could shed cadherins and could thereby relieve constraints on movement caused by adherens junctions. From Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading
matrix and non-matrix substrates. Cardiovasc Res February 15, 2006;69(3):614–24 with permission.
Cleaved collagen I,
ECM glycoproteins
aortic valve, in patients with Marfan syndrome [111]. Further, the interaction of AngII, monocyte chemoattractant protein-1
(MCP-1), calpain, transforming growth factor (TGF)-β1, tumor necrosis factor-α, and interleukin-1 with young VSMCs
boosts MMP-2 [112–118]. Taken together normal human aortic wall progresses with proinflammatory markers and is
marked by increased activation of MMPs [98].
MEDIA–VSMCS
In fact, VSMCs represent the major stromal cells of the vessel wall that is constantly exposed to biochemical mechanisms
and mechanical indicators of flow blood. Without doubt, VSMCs are implicated in all physiological and pathological processes of the vascular wall. To start with, VSMCs generate ECM during arterial wall growth that further confers the ability
to the arterial wall to resist high blood pressures. Moreover, VSMCs fix the injuries of the arterial wall [119]. Also, the
media is physiologically available to leucocytes [120,121], and it is allowing access to soluble plasma systems too [122].
The influence of aging on VSMCs is not debatable. Arterial aging alterations include the activation of the renin–
angiotensin–aldosterone system, modifications of VSMCs findings, altered regeneration of endothelial cells with
increased expansion, and movement of VSMCs with further aged vessel remodeling [123,124]. Also, consistent with
the actual evidence, VSMCs obtained from human atherosclerotic lesions senescence more rapidly in comparison
with VSMCs from normal vessels [125].
A noteworthy summary explanation looking at the influence of aging on VSMCs is shown in Fig. 1.5. In particular, the
age-associated disproportion with the dominant prooxidant state supports the inflammatory reaction; further with AngIIsignaling molecule formation by VSMCs, principally TGF-β1, MCP-1, and MMPs.
8 PART | I Overview
https://t.me/med1917
FIGURE 1.5 Schematic diagram illustrating some of the common and specific molecular pathways controlling vascular smooth muscle cell (VSMC)
phenotypic modulation in hypertension and aging. The CArG–SRF–myocardin axis plays a central role in maintaining the contractile state of VSMCs.
Its activity is modulated by Notch, Wnt, platelet-derived growth factor (PDGF), and transforming growth factor (TGF)-b signaling through the action
of the repressor factors, Herp1, Kruppel-like factor (KLF)4/5, and Elk1. A VSMC synthetic phenotype may result from increases in Ang II, intracellular
Ca2+, or stretch under the regulation of these specific transcriptional pathways. Arterial distensibility decreases with age but not in hypertension, which is
associated with the maintenance of arterial function. From Lacolley P, Regnault V, Nicoletti A, Li Z, Michel JB. The vascular smooth muscle cell in arterial
pathology: a cell that can take on multiple roles. Cardiovasc Res July 15, 2012;95(2):194–204 with permission.
To sum up, the age-related irremediable cellular senescence process leads to a gradual diminishing of the VSMCs
plasticity acting as a corresponding signaling process and with the increase in arterial stiffness [119]. Of importance, these
destructions are controlled by time alterations of telomeres due to the degenerative processes.
MEDIA–ELASTIN/COLLAGEN RATIO
The main etiology for aortic wall stiffness is the changes of the ratio elastin versus collagen with increase in collagen
proportion. Therefore, the collagen replaces elastin from tunica medie (thickest layer with elastic fibers and smooth muscle fibers) and penetrates overlying and underlying layers with the decrease in arterial elasticity. Undoubtedly, the highest increasing proportion of collagen causes premature senescence [126]. Furthermore, multiple studies corroborate this
hypothesis [127,128] and it was not surprising that studies on intima–media thickness show progressive thickening with
age [4,5,127,129].
Therefore, during the arterial wall stiffness process, the most important significant changes are the changing of ratio
between elastin and collagen that is done by the disorganization of VSMCs, modification of EMC, elastin fragmentation
Aging Aorta—Cellular Mechanisms Chapter | 1 9
https://t.me/med1917
FIGURE 1.6 High magnification of Masson trichrome/smooth muscle actin (SMA) staining in very young and very old aortic media. Aorta of the 3-year-old
child (left) shows a parallel and dense distribution of SMC between elastic fibers. In the aorta of 83-year-old man (right), there is a reduced number of SMC and
thick sporadic elastic fibers in an abundant connective tissue (SMA with Masson’s trichrome contrast staining, 400×). From Zarkovic K, Larroque-Cardoso P,
Pucelle M, Salvayre R, Waeg G, Nègre-Salvayre A, Zarkovic N. Elastin aging and lipid oxidation products in human aorta. Redox Biol 2015;2015(4):109–17
It is an open access article.
(Fig. 1.6) induced by MMP-2, MMP-1, MMP-9, and falling display of the tissue inhibitors of MMPs (TIMPs) [114,131].
Importantly, histological studies proved that there was destruction of the medial elastin of the proximal aorta with little
aging alteration in distal muscular arteries [4,123,128,132–134].
And, the association of elastin and collagen with VSMCs speeds up the stiffness of the aortic arterial wall. Moreover,
Boon et al. and Ott et al. showed recently that elastin degeneration is controlled by the combination of AngII and microRNA29 [135,136].
MEDIA INFLAMMATION
Arterial stiffening is correlated in different conditions with inflammation [137], even if inflammation does not have a
clear association with atherosclerosis [138]. However, severe inflammation is sufficient to trigger vascular inflammation [139]. Furthermore, previous work has been shown that aged vessels are correlated with eNOS uncoupling [63].
Besides, as mentioned earlier, there is a SASP represented by the secretion of proinflammatory biomarkers such as
proteases, cytokines, chemokines, growth factors, and soluble receptors that act via paracrine and/or autocrine way
[50,140]. Senescent VSMCs are associated with SASP and may cause a chronic low-grade inflammation for aging
vessels [3,141].
Moreover, proinflammatory stimuli and high-fat diet inhibit miR-181b expression in murine tissues, such as aorta
[142,143]. Of note, circulating miR-181b levels are also reduced in the elderly [144], suggesting that aging alters ath-
eroprotective miRNA expression in humans. Also, activation and nuclear translocation of the transcription factor nuclear
factor-κB (NF-κB) support vascular inflammation, atherosclerosis, and metabolic syndrome [145]. In contrast, activation
of SIRT1 restrains vascular inflammation [146–148].
TELOMERE LENGTH—A BIOMARKER OF AORTA AGING
Telomeres are one of the several key elements required for genomic stability [149,150]. An important feature is that telomeres have a protective role for chromosomes by avoiding enzymatic attrition, nonhomologous recombination, and end–
end fusion of chromosomal DNA. Telomeres are set as duplex loops, which include a double-stranded telomere loop
(T-loop) and a single-stranded (D-loop) (Fig. 1.7) [151,154,155].
10 PART | I Overview
https://t.me/med1917
FIGURE 1.7 The duplex structure of a telomere consisting of DNA forming a T-loop and D-loop. Several shelterin proteins bind specifically to the
telomeric DNA and facilitate telomere end protection and length control [151]. Shelterin complex core proteins—TRF1, 2—telomeric repeat-binding
factors; RAP1—human repressor activator protein 1; TIN2-TRF1—interacting protein; accessory binding proteins—Ku-the Ku70/Ku86 heterodimer,
tank-1, tank-2—tankyrase; MRE11/RAD50/NBS1-MRN DNA detection and repair complex, hnRNPs—heterogeneous nuclear ribonucleoprotein [152].
From Butt HZ, Atturu G, London NJ, Sayers RD, Bown MJ. Telomere length dynamics in vascular disease: a review. Eur J Vasc Endovasc Surg July
2010;40(1):17–26 with permission.
In summary, telomeres are protein structures represented by multiplying of the sequential nucleotides TTAGGG, which
are located at the distal end of the eukaryotic chromosomes to have a protective role in maintaining chromosome function
by preventing their structural degradation in the mitogenesis [149,156]. As a result, there is a consecutive shortening of telomeres with each cell division [157]. Consequently, short telomeres may generate the cellular senescence [158]. Tchirkov
and Lansdorp proposed the importance of both sufficient telomerase activity and maintenance of telomere length for aging
in primary human fibroblast [159]. Therefore, telomere integrity is controlled by telomerase that is composed from a
functional subunit of RNA and reverse transcriptase catalytic subunit [160], which by their activity maintains the balance
between telomeres length and telomeres shorten [161,162]. Shortening of telomeres due to different degenerative processes
is proved by human and experimental studies as being implied in the aging–cardiovascular disorders [163].
It must be underlined that in vessel wall, the telomeres length shortening is faster due to permanent stress produced by
contraction and relaxation of the aorta and other specific components. Furthermore, Benetos et al. (2001) have been shown
in a study population of 193 patients (120 men, 73 women) with a mean age of 56 ± 11 years, that in both genders, shortening of telomere was associated with age (P < .01) [164]. On the other hand, Mather et al. (2011) [165] examined over 3830
studies in which included was the main search criteria age and mortality in correlation with telomeres length by a question:
“Is Telomere Length a Biomarker of Aging?” (Table 1.2). Their conclusion was that telomere length as a biomarker of age
is equivocal and more studies are compulsory.
Numerous studies increasingly sustain a correlation between shorten telomere and raised tendency to cardiovascular
morbidity. On the other hand, only some studies confirm a direct correlation between shorten telomeres with vascular surgical disorders such as carotid stenosis, aortic aneurysm, and PVD (Table 1.3).
It has to be mentioned that the results of some studies from Table 1.3 [153] are debatable because they included only
patient cohorts over 85 years old. In this context, the decay of telomeres may additionally increase the vascular disease risk
alongside the abovementioned risk factors [180].
Despite the earlier evidence, multiple studies approached the corroboration between the significance of shorten telomeres with life span and mortality, for which the American Federation of Aging Research [182,183] has been introduced
that short telomeres are aging biomarkers, considering that telomere length is more faithful than chronological age.
Other mentioned mechanisms correlating the telomere decay with vascular disease comprise [47,184–187] the following: (1) fast cellular senescence may connect the telomere decay with disease development based upon the fact that
the senescent tissue is correlated with endothelial dysfunction and plaque instability; (2) high oxidative stress such as
smoking and hypertension causes oxidative DNA; (3) atherosclerotic disease is associated with entire inflammatory
Aging Aorta—Cellular Mechanisms Chapter | 1 11
https://t.me/med1917
Adjusted
For? TL Assay
No. of
Deaths
Follow-Up
(y)
27 ∼20 598 Age, sex Q-PCR
TRF
♂ analyzed
separately)
41 ∼7 176 Age, race, sex TRF
31 ∼7 156 Assay TRF
Continued
33 4.4 289 Age TRF
USA 143 Range 60–97 50 ∼20 101 Age Q-PCR
Details of
Result Sample n Age (Years) % ♂
P
Value
<.05* Individuals
with shorter
TL ∼2 × higher
mortality rate:
3 × higher mortal-
ity rate from
heart disease
(P = .008**) and
8 × higher mortal-
598 Range 85–101;
Leiden
ity rate from
infectious disease
(P = .015*)
>.40 Not associated
M age = 89.9
812 73–101 32 7–8 412 Age (♀ and
85 + study, The
Netherlands
spective study—
with all-cause
mortality
n.s. N/A Danish pro-
190 79 43 5 36 Sex, TL assay Q-PCR
singletons and
twins
Cohort 1921,
>.05 N/A Lothian Birth
419 Range 65–92;
Scotland,
prospective
.19 N/A Cardiovascular
M = 74.2
350 Range 63–95;
health study
subsample,
USA
Swedish twins
.03* ∼3 × higher
M = 79
(same sex)
mortality rate
for the co-twin
with shorter M
telomere length
M ∼79
548 Range 73–94;
Longitudinal
Study of Aging
Danish Twins
(same sex)
ity rate for the
co-twin with
shorter telomeres
in the lower
≤.014* Increased mortal-
25%–50% of the
telomere length
distribution
TABLE 1.2 Telomere Length and Mortality/Life Span Studies
Study
Cawthon
(2003) [166]
Martin-Ruiz
(2005) [167]
Bischoff 2006
[168]
Harris (2006)
[169]
Fitzpatrick
(2007) [170]
Bakaysa
(2007) [171]
Kimura
(2008) [172]
Соседние файлы в папке Библиотека им академика М.И. Перельмана