Role of Aldosterone and Mineralocorticoid Receptor in Cardiovascular Aging

Abstract

The mineralocorticoid receptor (MR) was originally identified as a regulator of blood pressure, able to modulate renal sodium handling in response to its principal ligand aldosterone. MR is expressed in several extra-renal tissues, including the heart, vasculature, and adipose tissue. More recent studies have shown that extra-renal MR plays a relevant role in the control of cardiovascular and metabolic functions and has recently been implicated in the pathophysiology of aging. MR activation promotes vasoconstriction and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Aging is associated with increased arterial stiffness and vascular tone, and modifications of arterial structure and function are responsible for these alterations. MR activation contributes to increase blood pressure with aging by regulating myogenic tone, vasoconstriction, and vascular oxidative stress. Importantly, aging represents an important contributor to the increased prevalence of cardiometabolic syndrome. In the elderly, dysregulation of MR signaling is associated with hypertension, obesity, and diabetes, representing an important cause of increased cardiovascular risk. Clinical use of MR antagonists is limited by the adverse effects induced by MR blockade in the kidney, raising the risk of hyperkalaemia in older patients with reduced renal function. Therefore, there is an unmet need for the enhanced understanding of the role of MR in aging and for development of novel specific MR antagonists in the context of cardiovascular rehabilitation in the elderly, in order to reduce relevant side effects.

Keywords: RAAS; endothelial dysfunction; mineralocorticoid receptor; oxidative stress; vascular stiffness.

Figure 1

Diagram represents signaling for the contribution of mineralocorticoid receptor (MR) in smooth muscle cell (SMC) to vascular aging. Rises in SMC-MR expression with aging suppress miR-155, leading to the up-regulation of angiotensin type 1 receptors (AgtR1) and L-type calcium channels (LTCC), resulting in increased calcium influx and reactive oxygen species (ROS) production. This signaling causes enhanced vasoconstriction and oxidative stress. Also, increased MR in SMC with aging contributes to transcriptional activation of pro-fibrotic genes, leading to increased vascular fibrosis. These structural and functional changes with aging via MR in SMC result in hypertension and vascular stiffening. CTGF, connective tissue growth factor; MMP2, matrix metalloproteinase-2; BMP4, bone morphogenetic protein-4; TGFβ, transforming growth factor beta; Col1a1, collagen type-1 alpha-1; Col3a1, collagen type-3 alpha-1; Cav1.2, calcium channel; voltage-dependent; L type, alpha 1C subunit.

Figure 2

Aging is associated with vascular damage characterized by inflammation, vascular thickening, arterial stiffness and overproduction of reactive oxygen species (ROS). In this setting, mineralocorticoid receptor (MR) activation in endothelial cells can contribute to amplify cardiovascular adverse outcomes, exacerbating vascular stiffness through the induction of augmented ROS production, vascular inflammation and collagen deposition, finally leading to endothelial dysfunction and atherosclerosis. eNOS, endothelial nitric oxide synthase; NOX4, NADPH Oxidase 4; ICAM1, Intercellular Adhesion Molecule 1; VCAM1, vascular cell adhesion molecule 1.