From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

Abstract

Inappropriately (relative to dietary Na + ) elevated plasma aldosterone concentrations (PAC), or aldosteronism, have been incriminated in both the appearance of the cardiometabolic syndrome (CMS) and its progressive nature. The deleterious dual consequences of elevated PAC and dietary Na + have been linked to several components of the CMS, including salt-sensitive hypertension. Moreover, their adverse consequences are considered to be synergistic, culminating in a pro-oxidant phenotype with oxidative injury involving the heart and systemic tissues, including peripheral blood mononuclear cells (PBMC). Our experimental studies in rats receiving aldosterone/salt treatment have identified a common pathogenic event that links aldosteronism to the induction of oxidative stress. Herein, we review these findings and the important role of excessive intracellular Ca 2+ accumulation (EICA), or intracellular Ca 2+ overloading, which occurs in the heart and PBMC, leading to, respectively, cardiomyocyte necrosis with a replacement fibrosis and an immunostimulatory state with consequent coronary vasculopathy. The origin of EICA is based on elevations in plasma parathyroid hormone, which are integral to the genesis of secondary hyperparathyroidism that accompanies aldosteronism and occurs in response to plasma-ionized hypocalcemia and hypomagnesemia whose appearance is the consequence of marked urinary and fecal excretory losses of Ca 2+ and Mg 2+ . In addition, we found intracellular Ca 2+ overloading to be intrinsically coupled to a dyshomeostasis of intracellular Zn 2+ , which together regulate the redox state of cardiac myocytes and mitochondria via the induction of oxidative stress and generation of antioxidant defenses, respectively. To validate our hypothesis, a series of site-directed, sequential pharmacological and/or nutriceutical interventions targeted along cellular-molecular cascades were carried out to either block downstream events leading to the pro-oxidant phenotype or to enhance antioxidant defenses. In each case, the interventions were found to be cardioprotective. These cumulative salutary responses raise the prospect that pharmacological agents and nutriceuticals capable of influencing extra-and intracellular Ca 2+ and Zn 2+ equilibrium could prevent adverse cardiac remodeling and thereby enhance the management of aldosteronism.

Eplerenone potentiates protective effects of amlodipine against cardiovascular injury in salt-sensitive hypertensive rats

“…Parathyroid hormone may induce intracellular Ca 2+ overloading and, subsequently, oxidative stress. 32,33 Moreover, recent experimental work on myocardially infarcted rats shows that under conditions of cardiac tissue damage, physiologic glucocorticoids can activate MR, and subsequently aldosterone becomes a minor player under such conditions. Further research is needed to elucidate the precise mechanism underlying the protective effects of eplerenone in salt-loaded Dahl rats with low plasma aldosterone.…”

Vitamin D deficiency is an independent predictor of mortality in patients with chronic heart failure

“…This response is exacerbated in people with 25[OH]D deficiency [30,31]. The consequences of 25[OH]D deficiency [32] and elevated PTH levels [33][34][35][36] are calcium loading, with cardiomyocyte and skeletal muscle contractile dysfunction, cellular hypertrophy, oxidative stress, immune activation, endothelial dysfunction (including enhanced endothelin-1 release) [30,34,[37][38][39][40][41]. These influences are reflected clinically with an increased risk of hospitalisation [7,42], and worsening renal function [43], whilst vitamin D supplementation may be associated with a reduction of plasma renin and aldosterone levels [44,45].…”

Molecular Biology of Atherosclerosis

“…Incubation of human endothelial cells with high glucose promotes mitochondrial ROS production and mitochondrial damage (815) and high fatty acid levels in diabetes is also likely to contribute to mitochondrial dysfunction (2000). Excess intracellular calcium levels associated with excessive aldosterone in the presence of relatively high salt intake may also contribute to mitochondrial ROS production (2116). Higher ROS may theoretically shift the balance of tyrosine kinases and phosphatases toward the inflammation-activating tyrosine kinases (868).…”