SIRT1 Overexpression in Perivascular Adipose Tissue Enhances Vasodilatation and Prevents Arterial Remodeling by Modulating Crosstalks between Mitochondria and Endoplasmic reticulum

Abstract

Introduction: SIRT1 is a NAD-dependent protein deacetylase and a member of the anti-ageing protein family of Sirtuins. The present experiments were designed to test the hypothesis that overexpressing SIRT1 in perivascular adipose tissue (PVAT) improves arterial structure and function. Aims: To study perivascular adipose tissue modulation of ER-mitochondria crosstalk and its effects on vascular function in transgenic mice. Methods: Mice with overexpression of human SIRT1 (Adipo-SIRT1) or its dominant negative H363Y mutant (Adipo-H363Y) selectively in adipose tissue have been established in the laboratory. From the age of four-weeks old, wild type (WT), Adipo-SIRT1 and Adipo-H363Y littermates were fed standard chow or high fat diet. At the age of 17-weeks, aortae and mesenteric arteries with or without the surrounding PVAT were isolated. Arterial structure and function were evaluated using both the Wire Myograph and Pressure Myograph systems (Danish Myograph Technology, Aarhus, Denmark). Mitochondria function and ER-mitochondria crosstalk were evaluated using MitoSOX assay and western blotting techniques respectively. Results: Compared to those of WT, overexpression of SIRT1 significantly enhanced the anti-contractile properties of PVAT and prevented dietary obesity-induced reduction of the relaxations to acetylcholine of arteries from Adipo-SIRT1 mice. By contrast, overexpression of H363Y caused severe adverse arterial remodeling in Adipo-H363Y mice, resulting in stiffening of arteries. Mechanistically, SIRT1 overexpression caused mild mitochondrial and endoplasmic Reticulum (ER) stresses, in turn triggering the production of reactive oxygen species (ROS) to mediate the vasoprotective effects of PVAT in Adipo-SIRT1 mice. However, overexpression of H363Y failed to initiate such cellular defense mechanisms. Conclusion: Modulation of SIRT1 function in PVAT represents an effective approach to maintain arterial structure and endothelium-dependent vasodilatations.