Resveratrol induces mitochondrial biogenesis in endothelial cells

Abstract

Pathways that regulate mitochondrial biogenesis are potential therapeutic targets for the amelioration of endothelial dysfunction and vascular disease. Resveratrol was shown to impact mitochondrial function in skeletal muscle and the liver, but its role in mitochondrial biogenesis in endothelial cells remains poorly defined. The present study determined whether resveratrol induces mitochondrial biogenesis in cultured human coronary arterial endothelial cells (CAECs). In CAECs resveratrol increased mitochondrial mass and mitochondrial DNA content, upregulated protein expression of electron transport chain constituents, and induced mitochondrial biogenesis factors (proliferator-activated receptor-coactivator-1α, nuclear respiratory factor-1, mitochondrial transcription factor A). Sirtuin 1 (SIRT1) was induced, and endothelial nitric oxide (NO) synthase (eNOS) was upregulated in a SIRT1-dependent manner. Knockdown of SIRT1 (small interfering RNA) or inhibition of NO synthesis prevented resveratrol-induced mitochondrial biogenesis. In aortas of type 2 diabetic (db/db) mice impaired mitochondrial biogenesis was normalized by chronic resveratrol treatment, showing the in vivo relevance of our findings. Resveratrol increases mitochondrial content in endothelial cells via activating SIRT1. We propose that SIRT1, via a pathway that involves the upregulation of eNOS, induces mitochondrial biogenesis. Resveratrol induced mitochondrial biogenesis in the aortas of type 2 diabetic mice, suggesting the potential for new treatment approaches targeting endothelial mitochondria in metabolic diseases.

Resveratrol and health – A comprehensive review of human clinical trials

“…The benefits of resveratrol for memory and prevention of neurodegenerative diseases is well documented in laboratory animals [74][75][76], and this aspect is only beginning to be explored through a number of ongoing human clinical trials ( Table 2 in Supporting Information). Resveratrol has been demonstrated to modulate mitochondrial biogenesis through activating PGC-1a [77,78], which may ultimately slow the aging process and prevent a number of chronic diseases [79] and improve muscular endurance [80]. Laboratory models have found resveratrol reduces oxidative stress in skeletal muscle following exercise [81] and disuse [82], and suppresses aging-associated decrements in physical performance [83], but does not attenuate sarcopenia [84].…”

Proenergetic effects of resveratrol in the murine neuronal cell line Neuro2a

“…Numerous studies in the literature also reported resveratrol protected cells from mitochondrial dysfunction [45][46][47]. Interestingly, resveratrol was found to increase the number of mitochondria in various cell lines and tissues, such as in Neuro2a cells [28], endothelial cells [56] and muscle [45]. In cultured human coronary arterial endothelial cells, resveratrol up-regulated protein expression of electron transport chain components, enhanced mitochondrial DNA content and mitochondrial mass, activated mitochondrial biogenesis factors (peroxisome proliferator-activated receptor- coactivator-1α PGC-1α, nuclear respiratory factor-1 NRF-1, mitochondrial transcription factor-A mtTF-A) [56].…”

“…In cultured human coronary arterial endothelial cells, resveratrol up-regulated protein expression of electron transport chain components, enhanced mitochondrial DNA content and mitochondrial mass, activated mitochondrial biogenesis factors (peroxisome proliferator-activated receptor- coactivator-1α PGC-1α, nuclear respiratory factor-1 NRF-1, mitochondrial transcription factor-A mtTF-A) [56]. Knockdown of NAD + -dependent protein deacetylase SIRT1 prevented resveratroltriggered mitochondrial biogenesis, suggesting that resveratrol elevated mitochondrial content in a SIRT1-dependent manner [56].…”

Sirtuins, aging, and cardiovascular risks

“…Resveratrol, a polyphenolic antioxidant found in red wine, activating SIRT1 (Villalba and Alcain 2012;Wallerath et al 2002) prevents oxidative stress and coronary VSMC proliferation inhibiting extracellular signal regulated kinase (ERK) activation (Chong et al 2012;El-Mowafy et al 2008). Recent biophysical data indicate that resveratrol interacts with and modulates SIRT1 activity via an allosteric mechanism (Cencioni et al 2015;Hubbard et al 2013;Sinclair and Guarente 2014); these findings interestingly indicate that micromolar levels of resveratrol are sufficient to exert vasculoprotective effects through SIRT1 action (Csiszar et al 2009;Della-Morte et al 2009;Pacholec et al 2010;Ungvari et al 2007;Yang et al 2013). However, some data have suggested that resveratrol seems more likely act through a complex indirect mechanism dependent on the inhibition of phosphodiesterases (PDE) paralleled by AMPK activation (Beher et al 2009;Cencioni et al 2015;Park et al 2012;Yang et al 2013).…”