From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation.
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.
Zia
Ayhan A
AA
Department of Medicine, Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Kamalov
German
G
Newman
Kevin P
KP
McGee
Jesse E
JE
Bhattacharya
Syamal K
SK
Ahokas
Robert A
RA
Sun
Yao
Y
Gerling
Ivan C
IC
Weber
Karl T
KT
D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006929:Hyperaldosteronism / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D018384:Oxidative Stress; D051381:Rats; D012964:Sodium / Q000378:metabolism; D014657:Vasculitis / Q000378:metabolism / Q000473:pathology; D015032:Zinc / Q000378:metabolism
D000450:Aldosterone; D012964:Sodium; D015032:Zinc; D002118:Calcium