SIRT3-MEDIATED MACROPHAGE PYRUVATE DEHYDROGENASE ACTIVITY IMPROVES PERIVASCULAR ADIPOSE TISSUE REMODELING IN HYPERTENSIVE MICE

Abstract

Objective: Infiltrated macrophages are a dominant population in the perivascular adipose tissue (PVAT) microenvironment and actively promote PVAT remodeling in hypertensive mice. However, the molecular mechanism underlying the role of macrophages in initiating metabolic inflammation remains uncertain. Here, we investigate whether Situin-3(SIRT3) is determinant in macrophage activation. Design and method: 10-week-old male WT, SIRT3 KO, and NLRP3 KO mice were infused with Angiotension II (Ang II, 1000ng/kg/min) or normal saline (NS) for 7 days. The morphological and functional changes of thoracic aorta and PVAT were determined by histological analysis and immunofluorescence staining. In vitro studies were performed on bone marrow-derived macrophages (BMDMs) and brown adipocytes isolated from WT or SIRT3 KO mice. Results: We report that Ang II accelerates PVAT inflammation and fibrosis in SIRT3-deficient mice. This effect is associated with attenuating browning markers and lipid droplet-associated protein expression. Immunofluorescence analysis confirmed that there is an increase in NLRP3 inflammasome and secretion of interleukin-1β (IL-1β). In vitro studies indicate that BMDMs from SIRT3 KO mice induce interleukin-IL-1β production by shifting metabolic phenotype from oxidative phosphorylation towards glycolysis. Mechanically, SIRT3 deacetylates and activates pyruvate dehydrogenase E1 alpha (PDHE1a) at lysine 83, loss of SIRT3 lead to decreased PDH activity, and accumulation of pyruvate and lactate metabolites. The PDHK inhibitor dichloroacetate (DCA) suppresses both pro-IL-1β maturation and caspase-1 activation in macrophages in response to Ang II. The blockade of IL-1β from macrophage into brown adipocytes restores expression of brown adipocyte specific markers. Coincidentally, NLRP3 KO mice exhibited a reduction in infiltrated macrophages in PVAT, while partially rescuing brown adipocytes mitochondrial function and collagen accumulation. Conclusions: Taken together, these findings reveal that SIRT3-mediated activity of PDHE1a inhibits macrophage activation. Pharmacological targeting of glycolysis metabolism may therefore represent an effective approach.