The Duality of Adiponectin and the Role of Sex in Atherosclerosis

Abstract

AbstractAdiponectin, a hormone highly abundant in circulation, has many beneficial effects in atherosclerosis; however, gene deficiency of this hormone or its receptor have shown detrimental effects on plaque burden in mice. Our objective was to understand the role of sex and aging in the effects of adiponectin deficiency on plaque content, inflammation, and the mechanisms regulating the phenotype ofadipoq-/-vascular smooth muscle cells (VSMCs). Even a 50% reduction in the expression of adiponectin led to a plaque reduction in males and an increase in females, compared withapoe-/-controls. Plaque reduction may be attributable to chemokines upregulated in males and downregulated in females. Changes in plaque were not attributed to changes in cholesterol or cardiovascular disease (CVD) markers. In old mice, both genotypes and sexes accumulated more plaque thanapoe-/-. RNA sequencing of VSMCs from male mice in vitro uncovered a critical role for adiponectin in AKT signaling, regulation of the extracellular matrix, and TGF-β signaling. Upregulation of AKT activity mediated proliferation and migration ofadipoq-/-cells. Activation of AMPK with metformin or AdipoRon reduced AKT-dependent proliferation and migration ofadipoq-/-cells but did not improve the expression of contractile genes. Anti-atherogenic mechanisms targeted the ECM inadipoq-/-cells, downregulating MMP2 and 9 and upregulating decorin.Our study uncovered sex and age-dependent effects of adiponectin deficiency in atherosclerosis.