**Acknowledgements**

and its downstream target, plasminogen activator inhibitor-1 (PAI-1), which promotes the

Loss of vascular smooth muscle cell (VSMC) function is an alarming sign of vascular disease. During the aging process, VSMCs undergo increased dysregulation, apoptosis, and senescence [64]. In VSMCs, SIRT1 can act as a modulator of neointima formation (associated with repression of activator protein-1 (AP-1) activity [63]) and protect against DNA damage. Aging-related loss of SIRT1 expression correlates with lower capacity for vascular repair,

Decreased expression of SIRT1 in VSMCs exerts its proatherogenic effects by the failure to deacetylate histones in DNA repair, response to oxidant stress and LDL, and therefore leads to VSMC senescence and apoptosis [63, 65]. As to atherosclerotic plaques, SIRT1 activity has been suggested to deacetylate the regulatory factor for X-box (RFX5) and antagonized repression of collagen type I (COL1A2) transcription in VSMCs, consequently stabilizing the plaque and avoiding rupture [66]. Another most recent finding relevant to destabilization of atherosclerotic plaque is that SIRT1 participated in downregulation of platelet-activating factor receptor (PAFR) in VSMCs through β-arrestin 2-mediated internalization and degradation, resulting in the inhibition of PAF-induced matrix metalloproteinase (MMP-2) generation [67]. In addition, inhibition of miR-138 was found to increase SIRT1 expression in VSMCs separated from diabetic (db/db) mice and in SMC lines C-12511 in recent study, which indicated miR-138 as another potential inhibitory target to attenuate the proliferation and migration of VSMCs and cure atherosclerosis [68]. Furthermore, SIRT1 was also found to inhibit angiotensin II-induced VSMC hypertrophy in rat embryonic aortic VSMCs [69]. Later on, SIRT1 demonstrated antihypertensive activity in transgenic mice with selective overexpression of SIRT1 in VSMCs (SV-Tg). Alleviated vascular remodeling in mouse thoracic and renal aortae induced by angiotensin II is observed, along with significantly decreased transforming growth factor-β1 (TGF-β1) expression, ROS generation, vascular inflammation, and collagen formation in the arterial wall of SV-Tg mice [70]. Similar to contribution in ECs, overexpression of miR-34a can upregulate p21 level and inflammation through SIRT1 downregulation and cause senescence-associated secretory phenotype factors induction (including proinflammatory molecules such as cytokines, chemokines, proteases, growth factors, soluble

receptors, etc.), promoting VSMC senescence and leading to arterial dysfunction [71].

**5. Targeting endothelial SIRT1 for the prevention of arterial aging**

Slowing down the vascular aging requires early intervention, lifelong treatment, and sitespecific approaches. To reduce arterial stiffness, pharmacological agents, including angiotensinconverting enzyme inhibitors, angiotensin II type 1 blockers, aldosterone antagonists, and statins, are currently available and in clinical use [35]. The evident vasoprotective effects of SIRT1 definitely pose great opportunities and challenges for drug discovery targeting endothelial dysfunction. So far, a few natural and synthetic substances have been demonstrated as SIRT1 activators to promote vascular health. The first potent activator of SIRT1 is resveratrol, a small polyphenol discovered in red wine, which could protect ECs against inflammation,

formation of neointima and vascular remodeling in response to vascular injury [40].

abolished stress response, and elevated senescence [63].

80 Endothelial Dysfunction - Old Concepts and New Challenges

This work was financially supported by Hong Kong Health and Medical Research Fund 13142651.
