The role of mineralocorticoid receptor signaling in the cross-talk between adipose tissue and the vascular wall

Abstract

Vascular dysfunction and impaired endothelial mediated relaxation are powerful underlying abnormalities in the pathogenesis of hypertension, coronary heart disease, and stroke. Obesity, type 2 diabetes mellitus, and other metabolic abnormalities are associated with activation of mineralocorticoid receptor (MRs) in the vasculature and adipose tissue. While MR signaling is involved in the normal physiological differentiation and maturation of adipocyte, enhanced activation of MRs also contributes to increase oxidative stress, release of pro-inflammatory adipokines, and dysregulation of adipocyte autophagy. This, in turn, increases the maladaptive expansion of subcutaneous, visceral and perivascular adipose tissue, resulting in systemic and cardiovascular (CV) insulin resistance and increased CV stiffness and impaired vascular and cardiac relaxation. This review summarizes the normal role of MR activation in adipose tissues and explores the mechanisms by which excessive MR activation mediates adipose tissue inflammation and vascular dysfunction. Potential preventative and therapeutic strategies directed in the prevention of MR activation and CV disease are also discussed.

Keywords: Adipocyte tissue; Adipokines; Cardiovascular disease; Metabolic disorders; Mineralocorticoid receptors; Obesity.

Figure 1

Proposed the role of mineralocorticoid receptor mediated the signaling in the cross-talk between adipose tissue and the vascular dysfunction. ECMR increases EnNaC surface abundance, intra-endothelial sodium, F actin polymerization and cell stiffness, leading to subsequent decreases in eNOS activation and NO bioavailability. Reduced NO decreases cGMP/PKG and activates kinases responsible for promotion of VSMC levels of intracellular Ca²⁺ and Ca²⁺ sensitization that induces impairment of vascular relaxation. Meanwhile, enhanced adipocyte MR activation promotes an increase in H₂O₂ and impaired VSMC contractility involving down-regulation of MLC kinase phosphorylation/activation and VSMC Ca²⁺ sensitivity contractile machinery. Furthermore, Over-nutrition and obesity decrease circulating adiponectin and increase the activation of MRs in PVAT, ECs, and VSMCs that prompts vascular oxidative stress. The increased ROS up-regulate adiponectin expression in PVAT via a PPAR-γ with a feedback manner, resulting in increases in eNOS activity and bioavailable NO. Abbreviations: MR, mineralocorticoid receptor; PVAT, perivascular adipose tissue; ECs, endothelial cells; VSMCs, vascular smooth muscle cells; ROS, reactive oxygen species; PPAR-γ, peroxisome proliferator-activated receptor γ; NO, nitric oxide; eNOS, endothelial NO synthase; ECMR, endothelial cell mineralocorticoid receptor; EnNaC, endothelial epithelial sodium channel; cGMP/PKG, cyclic guanosine 3′,5′-monophosphate/protein kinase G; Ca²⁺, calcium; H₂O₂, hydrogen peroxide; TG2, transglutaminase 2; P-MLC20, phosphorylated myosin regulatory light chain.

Figure 2

MR mediates chronic over-nutrition and activated renin–angiotensin-aldosterone system-induced adipogenesis through mTOR1/S6K1 signaling pathways. MR, mineralocorticoid receptor; mTOR, rapamycin; S6K, ribosomal S6 kinase; Akt, protein kinase B; PPAR-γ, peroxisome proliferator-activated receptor γ; C/EBPs, CCAAT-enhancer-binding proteins.