Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease

Abstract

The mineralocorticoid receptor (MR), a member of the steroid receptor family, regulates blood pressure by mediating the effects of the hormone aldosterone on renal sodium handling. In recent years, it has become clear that MR is expressed in vascular smooth muscle cells (SMC) and interest has grown in understanding the direct role of SMC MR in regulating vascular function. This interest stems from multiple clinical studies where MR inhibitor treatment reduced the incidence of cardiovascular events and mortality. This review summarizes the most recent advances in our understanding of SMC MR in regulating normal vascular function and in promoting vascular disease. Many new studies suggest a role for SMC MR-activation in stimulating vascular contraction, and contributing to vessel inflammation, fibrosis, and remodeling. These detrimental vascular effects of MR activation appear to be independent of changes in blood pressure and are synergistic with the presence of endothelial dysfunction or damage. Thus, in humans with underlying cardiovascular disease or cardiovascular risk factors, SMC MR activation may promote hypertension, atherosclerosis, and vascular aging. Further exploration of the molecular mechanisms for the effects of SMC MR activation has the potential to identify novel therapeutic targets to prevent or treat common cardiovascular disorders.

Aldosterone and the mineralocorticoid receptor in insulin resistance and diabetes

“…In the endothelium, MCR activation reduces nitric oxide production and increases reactive oxygen species (ROS) production through induction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. These actions initially cause endothelial dysfunction and ultimately impair insulin action at the target tissue [26][27][28] . In addition, MCR activation in vascular smooth muscle cells reduces the expression of insulin receptor substrate-1 (IRS-1) and downstream Akt signaling, directly inducing insulin resistance 29,30 .…”

Nuclear Receptors in Vascular Biology

“…Moreover, MR inhibitors clinically reduced the incidence of cardiovascular events and improve mortality rates [27]. MR is also expressed in vascular endothelial cells and smooth muscle cells [27].…”

“…Moreover, MR inhibitors clinically reduced the incidence of cardiovascular events and improve mortality rates [27]. MR is also expressed in vascular endothelial cells and smooth muscle cells [27]. Smooth muscle cell MR activation causes vasoconstriction and promotes vessel inflammation, fibrosis, and remodeling [27].…”

“…MR is also expressed in vascular endothelial cells and smooth muscle cells [27]. Smooth muscle cell MR activation causes vasoconstriction and promotes vessel inflammation, fibrosis, and remodeling [27]. In a model of high fat feeding induced endothelial cell dysfunction, endothelial cell expression of NADPH oxidase (subunits p22phox, p40phox), and impaired endothelial cell-dependent vasodilation were reversed by either an MR antagonist (eplerenone), or in endothelial cells specific MR knockout mice [28].…”

Aldosterone Does Not Predict Cardiovascular Events Following Acute Coronary Syndrome in Patients Initially Without Heart Failure

“…In heart failure, secretion of aldosterone may become maladaptive, promoting excessive sodium retention and blood volume. In addition, sustained high levels of aldosterone may exert direct adverse effects on the arterial wall by promoting vascular remodeling with fibrosis and calcification1, 2, 3 and in myocardium by decreasing contractility and promoting coronary vasoconstriction4, 5 and fibrosis that may provide the substrate for arrhythmias 6, 7, 8. Acting in the central nervous system, aldosterone may stimulate neural pathways that promote hypertension and sodium retention 9, 10, 11…”