Uncoupling the Coupled Calcium and Zinc Dyshomeostasis in Cardiac Myocytes and Mitochondria Seen in Aldosteronism

作者：Kamalov German; Ahokas Robert A; Zhao Wenyuan; Zhao Tieqiang; Shahbaz Atta U; Johnson Patti L; Bhattacharya Syamal K; Sun Yao; Gerling Ivan C; Weber Karl T^*

来源：Journal of Cardiovascular Pharmacology, 2010, 55(3): 248-254.

• aldosteronism
• calcium
• zinc
• cardiomyocytes
• mitochondria
• oxidative stress
• antioxidant defenses

Intracellular [Ca(2+)](i) overloading in cardiomyocytes is a fundamental pathogenic event associated with chronic aldosterone/salt treatment (ALDOST) and accounts for an induction of oxidative stress that leads to necrotic cell death and consequent myocardial scarring. This prooxidant response to Ca2+ overloading in cardiac myocytes and mitochondria is intrinsically coupled to simultaneous increased Zn(2+) entry serving as an antioxidant. Herein, we investigated whether Ca(2+) and Zn(2+) dyshomeostasis and prooxidant to antioxidant dysequilibrium seen at 4 weeks, the pathologic stage of ALDOST, could be uncoupled in favor of antioxidants, using cotreatment with a ZnSO(4) supplement; pyrrolidine dithiocarbamate (PDTC), a Zn(2+) ionophore; or ZnSO(4) in combination with amlodipine (Amlod), a Ca(2+) channel blocker. We monitored and compared responses in cardiomyocyte free [Ca(2+)](i) and [Zn(2+)](i) together with biomarkers of oxidative stress in cardiac myocytes and mitochondria. At week 4 of ALDOST and compared with controls, we found (1) an elevation in [Ca(2+)](i) coupled with [Zn(2+)](i) and (2) increased mitochondria. H(2)O(2) production and increased mitochondrial and cardiac 8-isoprostane levels. Cotreatment with the ZnSO(4) supplement alone, PDTC, or ZnSO(4)+Amlod augmented the rise in cardiomyocyte [Zn(2+)](i) beyond that seen with ALDOST alone, whereas attenuating the rise in [Ca(2+)](i), which together served to reduce oxidative stress. Thus, a coupled dyshomeostasis of intracellular Ca(2+) and Zn(2+) was demonstrated in cardiac myocytes and mitochondria during 4-week ALDOST, where prooxidants overwhelm antioxidant defenses. This intrinsically coupled Ca(2+) and Zn(2+) dyshomeostasis could be uncoupled in favor of antioxidant defenses by selectively increasing free [Zn(2+)](i) and/or reducing [Ca(2+)](i) using cotreatment with ZnSO(4) or PDTC alone or ZnSO(4)+Amlod in combination.

• 出版日期2010-3