Adipocyte-Specific Mineralocorticoid Receptor Overexpression in Mice Is Associated With Metabolic Syndrome and Vascular Dysfunction: Role of Redox-Sensitive PKG-1 and Rho Kinase

Abstract

Mineralocorticoid receptor (MR) expression is increased in adipose tissue from obese individuals and animals.We previously demonstrated that adipocyte-MR overexpression (Adipo-MROE) in mice is associated with metabolic changes. Whether adipocyte MR directly influences vascular function in these mice is unknown. We tested this hypothesis in resistant mesenteric arteries from Adipo-MROE mice using myography and in cultured adipocytes. Molecular mechanisms were probed in vessels/vascular smooth muscle cells and adipose tissue/adipocytes and focused on redox-sensitive pathways, Rho kinase activity, and protein kinase G type-1 (PKG-1) signaling. Adipo-MROE versus control-MR mice exhibited reduced vascular contractility, associated with increased generation of adipocyte-derived hydrogen peroxide, activation of vascular redox-sensitive PKG-1, and downregulation of Rho kinase activity. Associated with these vascular changes was increased elastin content in Adipo-MROE. Inhibition of PKG-1 with Rp-8-Br-PET-cGMPS normalized vascular contractility in Adipo-MROE. In the presence of adipocyte-conditioned culture medium, anticontractile effects of the adipose tissue were lost in Adipo-MROE mice but not in control-MR mice. In conclusion, adipocyte-MR upregulation leads to impaired contractility with preserved endothelial function and normal blood pressure.Increased elasticity may contribute to hypocontractility. We also identify functional cross talk between adipocyte MR and arteries and describe novel mechanisms involving redox-sensitive PKG-1 and Rho kinase. Our results suggest that adipose tissue from Adipo-MROE secrete vasoactive factors that preferentially influence vascular smooth muscle cells rather than endothelial cells. Our findings may be important in obesity/ adiposity where adipocyte-MR expression/signaling is amplified and vascular risk increased.

Effect of the mineralocorticoid receptor antagonist eplerenone on liver fat and metabolism in patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled trial (MIRAD trial)

“…8,10,31,32 Accordingly, activation of the MR in adipocytes and the liver has been associated with increased hepatic expression of profibrotic markers, whereas MRA treatment attenuated this expression and reversed hepatic steatosis. 8,[31][32][33] Recent observational data indicate that hyperglycaemia and NAFLD are important risk factors for fibrosis, 34 and we observed a fibrosisreducing effect of eplerenone in the subgroup of patients with NAFLD at baseline using the two recommended biochemical fibrosis scores. 20 However, in the post hoc analysis, we could not draw any firm conclusions in this regard from the current study.…”

Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury

“…In patients with primary aldosteronism, adiponectin expression is reduced in adipose tissue; in vitro studies demonstrate that aldosterone decreases the production of this adipokine in adipocytes (16,17). MR expression is increased in adipose tissues of obese individuals and animals, facilitating the development of cardiometabolic syndrome and vascular dysfunction (18,19). Systemic MR antagonism improves adipose tissue function and metabolic performance in mice with either genetic or dietary obesity (20,21).…”

Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets

“…Therefore, the beneficial effects of MR antagonists observed in the previous experimental settings could, in theory, originate from the blockade of aldosterone signalling either in the vasculature or in AT (or both). Recent work has addressed this issue by utilizing an AT‐specific MR‐overexpressing mouse model; the direct action of aldosterone on AT was associated with metabolic syndrome, insulin resistance, a pro‐inflammatory phenotype of the AT and paracrine effects of PVAT on the vasculature (Nguyen Dinh Cat et al , ). These findings identify aldosterone as a link between AT and vascular biology.…”