Anti‐contractile activity of SIRT1 in the perivascular adipose tissue

Abstract

Background ˗ Perivascular adipose tissue (PVAT) reduces the contraction of blood vessel at least in part by secreting transferable relaxing factors. Nevertheless, the molecular mechanisms underlying PVAT-mediated anti-contractile activity remain uncharacterized. The present study examined the role of SIRT1, a longevity regulator, in modulating the anti-contractile effects of PVAT. Methods and Results ˗ Mesenteric arteries with or without the attached PVAT were isolated from wild type animals (WT), or mice with selective overexpression of human SIRT1 in adipose tissues (Adipo-SIRT1). Wire myography was performed to examine phenylephrine-induced arterial contractions. PVAT derived from Adipo-SIRT1 exhibited dose- and time-dependent anti-contractile activity, which was not affected by feeding the animals with high fat diet. Molecular analyses revealed that overexpression of SIRT1 decreased the expression of Triadin, an important component of the calcium-releasing ryanodine receptor (RyR) channels. Treatment with dantrolene sodium, an inhibitor of RyR, increased the anti-contractile activity of PVAT derived from WT. Mechanistically, SIRT1-triggered mitochondrial hormesis via modulating the calcium flux from endoplasmic reticulum. The increased production of mitochondrial reactive oxygen species (mtROS) was critically involved in SIRT1-mediated anti-contractile activity of PVAT. The beneficial function of SIRT1 in PVAT was abolished in transgenic mice with selective overexpression of Triadin in adipose tissues (Adipo-TRDN). Conclusions ˗Increased SIRT1 expression in PVAT promotes vascular anti-contraction at least partly through down regulation of Triadin-mediated calcium signaling.