Loss of Bcl-2 During the Senescence Exacerbates the Impaired Angiogenic Functions in Endothelial Cells by Deteriorating the Mitochondrial Redox State

Abstract

Abstract-Ageing is an important risk factor for ischemic cardiovascular diseases, although its underlying molecular mechanisms remain to be elucidated. Here, we report a crucial role of Bcl-2 in the impaired angiogenic functions in senescent endothelial cells (ECs) by modulating the mitochondrial redox state. Cellular senescence impaired angiogenic functions in ECs without attenuating the mitogen-activated protein kinase or Akt signaling, and vascular endothelial growth factor receptor 2 or Tie-2 expressions. We identified that Bcl-2 expression was markedly reduced in 3 independent models for senescent ECs, and pharmacological inhibition, as well as small interfering RNA-mediated gene silencing of Bcl-2, significantly impaired the angiogenic functions in young ECs. Bcl-2 has an antioxidative role by locating the glutathione at mitochondria, and we found that mitochondrial oxidative stress was significantly augmented in senescent ECs, in association with reduced mitochondria-associated glutathione. Transfection of Bcl-2 in senescent ECs significantly reduced the mitochondrial oxidative stress, restored the mitochondrial membrane potential, and improved the angiogenic capacity. Furthermore, gene transfer of Bcl-2 using adenovirus significantly improved the in vivo angiogenesis in the Matrigel plugs implanted into aged mice, whereas the Bcl-2 inhibitor reduced the angiogenesis in the Matrigel plugs implanted into young mice. Together, Bcl-2 plays a crucial role in the regulation of the mitochondrial redox state in ECs, and, thus, loss of Bcl-2 during the senescence exacerbates the impaired angiogenesis by augmenting the mitochondrial oxidative stress.

MiR-106b and MiR-15b Modulate Apoptosis and Angiogenesis in Myocardial Infarction

“…So, these results raised a new issue to further study the molecular mechanisms involve in modulatory activity of miR-15b on VEGF and Ang2 expression. Further, BCL2 is not a mediator in the angiogenic process of BP classification in GO; however, many studies suggested its functional role in promoting angiogenesis [52,53]. In our results, BCL2 gene is potentially suppressed by miR-15b through bioinformatic prediction.…”

Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats

“…Increased mitochondrial oxidative stress has been shown to impair angiogenic functions (90) and promote apoptosis in endothelial cells. We tested the hypothesis that the marked anti-oxidative action of CR is associated with pro-angiogenic and anti-apoptotic endothelial effects.…”

Cyclin-Dependent Kinase 5–Mediated Hyperphosphorylation of Sirtuin-1 Contributes to the Development of Endothelial Senescence and Atherosclerosis

“…1 In aged animals and elderly human subjects, the arterial endothelium exhibits morphological features of cellular senescence: flat and enlarged multinuclear endothelial cells that show positive staining of senescence-associated ␤-galactosidase (SA-␤-gal). [2][3][4][5][6] Cellular senescence correlates with aging-induced endothelial dysfunction and decreased production of endotheliumderived vasodilators such as nitric oxide and prostacyclin. [7][8][9] Moreover, senescent endothelial cells are proinflammatory and proatherosclerotic and have a decreased regenerative capacity.…”