Regulation of vascular tone by adipose SIRT1

Abstract

Abstract of thesis entitled: Regulation of Vascular Tone by Adipose SIRT1” Submitted by: Daniels KONJA For the degree of: Doctor of Philosophy The University of Hong Kong September, 2022

Background: Renewed interest in adipose tissue biology has led to its reclassification as an important endocrine organ, rather than an inert energy depot as previously conceived, that influences other tissues and organs through its bioactive secretome. The heart and most blood vessels, for example, are in direct contact with adipose tissues, from which they receive both structural and functional adaptive cues under different pathophysiological conditions. Perivascular adipose tissue-derived contraction and relaxing factors typically modulate blood vessel tone. SIRT1 is the first member of a family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases. As a longevity regulator, SIRT1 is a key energy sensor controlling cellular responses to nutrient availability and in turn protecting against ageing-related metabolic diseases.

Objectives: Previous studies have shown that, SIRT1 in adipose tissues enhances adipocyte metabolic functions and is protective against aging and obesity-associated metabolic abnormalities. The present study investigated the beneficial metabolic function of adipose SIRT1 in the context of perivascular adipose tissues, to the underlying vasculature, and the mechanisms of the vascular regulatory effects of adipose SIRT1.

Methods: Male wild type (WT) mice, mice with selective overexpression of human SIRT1 in adipose tissues (Adipo-SIRT1), mice with selective overexpression of the negative dominant human SIRT1(H363Y) in adipose tissues (Adipo-H363Y), mice with selective overexpression of human Triadin in adipose tissues (Adipo-TRDN), and a crossbreed of Adipo-SIRT1 and Adipo-TRDN mice (Adipo-TRDNAdipo-SIRT1) were generated and maintained for this study. All animals had free access to water and either standard mouse chow (STC), or where necessary, mice were fed with high-fat diet (HFD) for 12-weeks starting from the age of five-weeks old. Body weights, fat masses, circulating glucose and insulin sensitivity tests were carried out periodically. Results: The study results showed that, adipose SIRT1 enhances PVAT anticontractile activity through increased mitochondrial ROS production. The initial undesirable increased ROS production, was necessary to instigate mitohormesis by activating mitochondrial stress response signaling, as scavenging the ROS with mitochondria-targeting antioxidants attenuated the observed PVAT anticontraction. Mechanistic studies showed that, adipose SIRT1 overexpression in adipose tissues upregulates intracellular calcium release channels, particularly RyR, expression and activity. This induces mitochondrial Ca2+ overload and enhance ROS production. Mitochondrial hormesis, an adaptive stress response mechanism is activated in response to increased ROS production, with consequent changes in PVAT secretory phenotype that enhances PVAT anticontractile function. Inhibition of Ca2+-flux into mitochondria, and/or scavenging mitochondrial ROS, abolished mitohormesis and attenuated PVAT anticontractile activity. Modulation of intracellular Ca2+ release complexes by adipose SIRT1 was shown to be via differential regulation of triadin, a member of the RyR Ca2+ release complex, by suppressing the expression or activity of low molecular weight (Trisk51) isoform while upregulating high molecular weight (full length Trisk95) triadin to enhance its interaction with the RyR.

Conclusion: Altogether, the study demonstrated that, adipose SIRT1 regulates vascular tone by modulating intracellular calcium handling machinery to increase mitochondrial output, which activates mitohormesis and promotes beneficial PVAT secretory phenotype to enhance its anticontractile activity.