SIRT1 Promotes Proliferation and Prevents Senescence Through Targeting LKB1 in Primary Porcine Aortic Endothelial Cells

Abstract

Under conditions that cause endothelium injury, such as hypertension, high cholesterol levels and turbulent blood flow, replication of endothelial cells is increased for regenerating the damaged endothelium. 3 However, the regenerated endothelial cells usually reach replicative senescence after a finite number of cell replication. Senescent endothelial cells show diminished vasomotor-regulatory activities and elevated expression of proinflammatory molecules, which contribute to the development of age-associated cardiovascular diseases, such as atherosclerosis. 4 SIRT1 is a class III deacetylase implicated in a wide range of cellular functions. 5 This protein has attracted enormous interest since the discovery of the potential antiaging activities of its yeast homolog, Sir2. In mammalian system, the beneficial activities of SIRT1 against aging diseases, such as those related to neuro-and cardioprotection, have been suggested by many studies. 5,6 Cardiovascular aging represents the largest portion of age-related morbidity and mortality. Therefore, it is particularly important to elucidate whether SIRT1 exerts any antiaging effects in the cardiovascular system.

SIRT1 Overexpression Maintains Cell Phenotype and Function of Endothelial Cells Derived from Induced Pluripotent Stem Cells

“…The finding that SIRT1 overexpression improves iPSC-EC performance in our investigation agrees with studies by others on primary ECs, which may provide a mechanistic insight to our findings [14,21,22]. A previous study concluded that SIRT1 influences EC proliferation and prevents senescence by promoting the deacetylation, ubiquitination, and proteasome-mediated degradation of LKB1, a serine/ threonine kinase and tumor suppressor [14].…”

“…A previous study concluded that SIRT1 influences EC proliferation and prevents senescence by promoting the deacetylation, ubiquitination, and proteasome-mediated degradation of LKB1, a serine/ threonine kinase and tumor suppressor [14]. In another study, inhibition of SIRT1 activity in ECs resulted in a premature senescent-like phenotype through an increased p53 acetylation in parallel with an increased plasminogen activator inhibitor-1 (PAI-1) expression and decreased eNOS expression [22].…”

“…Moreover, SIRT1 plays various roles in maintaining endothelial function, including angiogenesis through deacetylation of the forkhead transcription factor (FOXO1) [12]; nitric oxide (NO) production through deacetylating and activating endothelial nitric oxide synthase (eNOS) [13]; cell proliferation by targeting the LKB1-AMPK pathway [14]; and inhibiting oxidative stress through p53 deacetylation [15,16]. Based on the various roles of SIRT1 in maintaining endothelial homeostasis, we hypothesize that overexpression of SIRT1 in iPSC-ECs would reduce senescence during in vitro culture, thereby maintaining EC phenotype and improving proliferative capacity.…”

Calorie restriction and sirtuins revisited

“…Among the important substrates deacetylated by SIRT1 in endothelial cells (ECs) are eNOS (Mattagajasingh et al 2007), LKB1 (Zu et al 2010), Notch (Guarani et al 2011), and p66shc . The net effect of SIRT1 in ECs appears to be control of vessel growth (Potente et al 2007) and protection against EC senescence (Ota et al 2007) and, more generally, atherosclerosis.…”

FOXOs and Sirtuins in Vascular Growth, Maintenance, and Aging

“…Moreover, SIRT1 safeguards ECs from senescence by preventing prolonged LKB1 AMPK signaling through LKB1 deacetylation and degradation. 90 Interestingly, AMPK enhances SIRT1 activity by elevating NAD ϩ levels, 91,92 suggesting that LKB1 AMPK and SIRT1 engage in a negative feedback loop that prevents sustained LKB1 AMPK activation ( Figure 5). Recent studies also illustrated that SIRT1 suppresses the expression of p66SHC, an adaptor protein whose inactivation protects mice from agingassociated vascular disease.…”