Rhynchophylline as an agonist of sirtuin 3 ameliorates endothelial dysfunction via antagonizing mitochondrial damage of endothelial progenitor cells.

Abstract

Background and purpose: Mitochondrial dysregulation of endothelial progenitor cells (EPCs) has been implicated in endothelial destruction and hypertension. Regulation of silent information regulator 3 (sirtuin 3; SIRT3) in mitochondrial damage of EPCs and the underlying molecular mechanisms remain unclear, and evidence of selective SIRT3 agonists for the treatment of hypertension also is lacking.

Experimental approach: Here, we discovered a potent SIRT3 agonist, rhynchophylline (Rhy), and explored its underlying action on mitochondrial damage of EPCs and endothelial dysfunction.

Key results: In spontaneously hypertensive rats, Rhy reduced blood pressure and ameliorated vasomotion, paralleling improved EPC function in the peripheral circulation. Moreover, Rhy alleviated mitochondrial damage and inhibited apoptosis via the mitochondrial apoptotic pathway. SIRT3 knockdown interrupted the regulation of mitochondrial homeostasis induced by Rhy, thus abolishing its antagonizing effect on EPC dysfunction and endothelial damage, suggesting that Rhy protection of EPC mitochondria is mediated via the activation of SIRT3. Rhy restrained the production of mitochondrial ROS and improved the activity of superoxide dismutase 2 (SOD2) in a SIRT3-dependent manner, whereas silencing SOD2 eliminated the inhibition by Rhy of oxidative stress and apoptosis, reflecting that SOD2 was indispensable for the regulation of Rhy on mitochondrial dysfunction and the mitochondrial-mediated apoptosis pathway.

Conclusion and implications: SIRT3-dependent mitochondrial homeostasis contributes to attenuating hypertension-related EPC dysfunction and endothelial injury, and Rhy itself is a potent and targeted SIRT3 agonist that prevented mitochondrial dysfunction by regulating the SIRT3/SOD2 pathway, which may provide new clues for drug candidates for hypertension therapeutics.