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

2010; Springer Nature; Volume: 33; Issue: 11 Linguagem: Inglês

10.1038/hr.2010.159

1348-4214

Ayhan A. Zia, German Kamalov, Kevin P. Newman, Jesse E. McGee, Syamal K. Bhattacharya, Robert A. Ahokas, Yao Sun, Ivan Gerling, Karl T. Weber,

Thyroid Disorders and Treatments

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 Ca2+ accumulation (EICA), or intracellular Ca2+ 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 Ca2+ and Mg2+. In addition, we found intracellular Ca2+ overloading to be intrinsically coupled to a dyshomeostasis of intracellular Zn2+, 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 Ca2+ and Zn2+ equilibrium could prevent adverse cardiac remodeling and thereby enhance the management of aldosteronism.