**1. Arterial aging**

Chronological age is associated with a progressive alteration of arterial structure and function, herein referred to as arterial aging, which contributes to the development of a wide range of cardiovascular diseases including hypertension, atherosclerosis, heart failure, and stroke [1–3]. Arterial system is composed of three types of arteries including large elastic or conduit arteries, medium-sized muscular arteries, and small arteries referred to resistance arteries. Arterial aging is characterized by endothelial dysfunction and arterial remodeling, indicating a decline in arterial elasticity/distensibility, decreased arterial compliance, and increased arterial stiffness. Physiological alterations of the vascular wall are dynamic and occur throughout life [4]. During aging, gradual thickening of the arterial wall, changes in wall composition (i.e., elastin fragmentation and collagen deposition), and an increase of artery diameter are observed in conduit arteries [2]. Increased intimal-to-media thickness (IMT) is a valid

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indicator of arterial aging supported by the finding that the IMT of the carotid artery increases twofold to threefold between 20 and 90 years of age [4]. Pulse wave velocity (PWV) is a noninvasive measure of vascular stiffness. Stiffening of the conduit arteries leads to increased aortic pulse pressure and increased PWV, which occurs in both sexes along aging [5].

ADP-ribosyltransferation, desuccinylation, and demalonylation [19]. Sirtuins regulate energy homeostasis, stress resistance, circadian rhythmicity, mitochondrial functions, and embry-

Targeting Endothelial SIRT1 for the Prevention of Arterial Aging

http://dx.doi.org/10.5772/intechopen.73019

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Human SIRT1 gene is located at chromosome 10q21.3 containing 11 exons with a total length of 33,715 base pair [21]. SIRT1 is composed of 747 amino acids including a core catalytic domain consisting of 275 amino acids and both N- and C-terminal extensions spanning about 240 amino acids [22]. There are two nuclear localization signals and two nuclear exportation signals located in the extensions whose balanced functionality determines the presence of SIRT1 in either the nucleus or cytoplasm and explains the distinct location of SIRT1 among

Regulation of SIRT1 enzymatic activity occurs at various levels including post-translational modification, protein complex formation, transcriptional regulation, and concentrations of enzymatic substrates [19, 24]. Phosphorylation of SIRT1 represents the major form of post-translational modifications. Independent studies report multiple phosphorylation sites by distinct proteins, including c-Jun N-terminal kinase 1 (Ser27/47), cyclin B/cyclin-dependent kinase 1 (Thr530, Ser540), casein kinase 2 (Ser659/661), and adenosine 5′-monophosphate-activated protein kinase (AMPK) (Thr344) [25–28]. Additional post-translational modifications include methylation by SET7/9 [29], nitrosylation by glyceraldehyde-3-phosphate dehydrogenase [30], and sumoylation by sentrin-specific protease 1 [31]. In addition, several endogenous protein-binding partners of SIRT1 are found to regulate its function via forming protein complex. For example, the active regulator of SIRT1 can bind to amino acids 114–217 in the N-terminus of SIRT1 and stimulate deacetylation of p53 in vivo [32]. On transcriptional level, SIRT1 was reported that nicotinamide phosphoribosyltransferase (NAMPT) upregulated the expression of SIRT1 and SIRT1 antisense long noncoding RNA, thus regulating senescence, proliferation, and migration of endothelial progenitor cells (EPCs) [33]. SIRT1 activity is also thought to be affected by the levels of intracellular co-substrate nicotinamide adenine dinucleotide (NAD+) and its product nicotinamide [34].

With age, SIRT1 expression in ECs is progressively downregulated. Overexpression of SIRT1 in the endothelium prevents cellular senescence, enhances vasodilatory responses, and attenuates aging-induced vascular damages [35–37]. The subsequent review will summarize the recent progresses related to the molecular regulation of SIRT1 expression in ECs and the anti-vascular

Apart from histones, SIRT1 can mediate the deacetylation of various signaling substrates to exert vasoprotective functions. SIRT1 is abundant in ECs mediating postnatal blood vessel growth via Foxo1 and helps to maintain endothelial function [38]. In vitro experiments showed that downregulation of SIRT1 using small interfering RNA (siRNA) uniquely inhibited endothelial sprout formation via a three-dimensional assay, while other mammalian sirtuin family members (SIRT2–SIRT7) could not [38]. In addition, the reduction of matrix metalloproteinase-14

aging effects of SIRT1 by focusing on endothelial dysfunction and arterial remodeling.

**3. SIRT1 in endothelial cells: molecular targets and biological** 

onic development, which in turn contribute to increased lifespan [20].

different cell lines and tissues [23].

**functions**

The endothelium, a monolayer of flattened, polygonal cells lining the inner surface of arteries, plays an important role in regulating arterial structure and function. The endothelium can respond to pathophysiological signals by producing various factors that regulate vascular tone, cellular adhesion, thromboresistance, smooth muscle cell proliferation, and inflammation. During arterial aging, senescence, activation, and dysfunction of endothelial cells (ECs) represent the earliest abnormalities that lead to an impaired endothelium-dependent vasodilatation and adverse arterial wall remodeling [6]. Senescent ECs undergo permanent growth arrest, get enlarged and flattened in morphology, and also display positive staining for senescence-associated β-galactosidase (SA-β-gal) [7]. There are mainly two types of senescence. One is caused by successive cell duplication as a kind of natural aging process termed as "replicative senescence" and characterized by shortening of telomere [8]. The other is called "premature senescence" and induced by several stress conditions such as oxidative stress, radiations, and exposure to oncogenes [9]. Endothelial activation is defined as the initial event in atherogenesis. Circulating proinflammatory molecules including cytokines (i.e., tumor necrosis factor-α (TNF-α)) or modified lipoproteins (i.e., oxidized low-density lipoprotein (oxLDL)) activates ECs to express chemokines, cytokines, and adhesion molecules, thus attracting and recruiting inflammatory cells such as macrophages and T cells. Both endothelial senescence and activation can induce endothelial dysfunction which is reflected by impairment of endothelium-dependent vasorelaxation caused by a loss of nitric oxide (NO) bioavailability in the vessel wall and altered anticoagulant and anti-inflammatory properties of the endothelium. Impaired endothelium-dependent vasodilation in the coronary circulation of humans has profound prognostic implications in that it predicts adverse cardiovascular events and long-term outcomes [1, 2, 10, 11].

Age-related loss of arterial functions has been demonstrated, and underlying mechanisms were studied in human studies. Reduced NO bioavailability in older age was reported by observing diminished forearm vasoconstrictor response to infusion of NO-synthase inhibitor L-NMMA in resistance arteries [12]. In older adults, supplementation of NO precursor, l-arginine, improves coronary artery blood flow response to acetylcholine [13] and skin blood flow response to whole body heating [14]. Moreover, age-related decline in synthesis of tetrahydrobiopterin, a co-factor in NO production, provides further evidence for impairment of vasodilation NO-pathway during aging [15]. In the aspect of vasoconstrictor pathways, a greater lower limb vasodilatation response to endothelin (ET)-receptor blockade in old men was reported [16]. A small but significant age-related impairment in vascular smooth muscle function was also observed in conduit and resistance arteries in a meta-analysis [17].
