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

Abstract

Intracellular [Ca2+]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 Zn2+ entry serving as an antioxidant. Herein, we investigated whether Ca2+ and Zn2+ dyshomeostasis and prooxidant:antioxidant dysequilibrium seen at 4 wks, the pathologic stage of ALDOST, could be uncoupled in favor of antioxidants, using cotreatment with a ZnSO4 supplement, pyrrolidine dithiocarbamate (PDTC), a Zn2+ ionophore, or ZnSO4 in combination with amlodipine (Amlod), a Ca2+ channel blocker. We monitored and compared responses in cardiomyocyte free [Ca2+]i and [Zn2+]i together with biomarkers of oxidative stress in cardiac myocytes and mitochondria. At wk 4 ALDOST and compared to controls, we found: i) an elevation in [Ca2+]i coupled with [Zn2+]i; and ii) increased mitochondrial H2O2 production, and increased mitochondrial and cardiac 8-isoprostane levels. Cotreatment with the ZnSO4 supplement alone, PDTC, or ZnSO4+Amlod augmented the rise in cardiomyocyte [Zn2+]i beyond that seen with ALDOST alone, while attenuating the rise in [Ca2+]i which together served to reduce oxidative stress. Thus, a coupled dyshomeostasis of intracellular Ca2+ and Zn2+ was demonstrated in cardiac myocytes and mitochondria during 4 wks ALDOST, where prooxidants overwhelm antioxidant defenses. This intrinsically coupled Ca2+ and Zn2+ dyshomeostasis could be uncoupled in favor of antioxidant defenses by selectively increasing free [Zn2+]i and/or reducing [Ca2+]i using cotreatment with ZnSO4 or PDTC alone or ZnSO4+Amlod in combination.

Cellular and molecular pathways to myocardial necrosis and replacement fibrosis

“…This divalent cation dyshomeostasis seen in muscular dystrophy could be prevented by parathyroidectomy or a Ca 2+ channel blocker. Furthermore, our findings with ALDOST resemble the protective role of increased [Zn 2+ ] i induced by a Zn 2+ supplement or Zn 2+ ionophore, when intracellular [Ca 2+ ] i overloading of the heart is present [80]. …”

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

“…89 Later, we investigated whether Ca 2+ and Zn 2+ dyshomeostasis and pro-oxidant:antioxidant disequilibrium seen at 4 weeks, the pathological stage of ALDOST, could be uncoupled in favor of antioxidants, using co-treatment with a ZnSO 4 supplement (see Figure 5) 4 , PDTC and ZnSO 4 +amlodipine were cardioprotective and attenuated necrosis and myocardial scarring. 13,62,98 Thus, the intrinsically coupled dyshomeostasis of intracellular Ca 2+ and Zn 2+ found in cardiac myocytes and mitochondria during 4 weeks ALDOST 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 , PDTC alone or ZnSO 4 +amlodipine in combination. Each of these interventions proved to be cardioprotective.…”

Calcium and zinc dyshomeostasis during isoproterenol-induced acute stressor state

“…Relative to the heart, we do not believe this to be the case given that the activity of Zn 2ϩ transporters needed for Zn 2ϩ entry and intracellular Zn 2ϩ accumulation would be lost to cardiomyocyte necrosis. This contrasts to ZnSO 4 supplement given as pretreatment before Isop (25) or with the salutary responses to this supplement when given to prevent the chronic cardiotoxicity associated with diabetes or aldosterone/salt treatment (32,42,60). Finally, the rise in total antioxidant capacity found in heart and plasma, including those derived from vitamins A, C, and E, was not adequate to prevent the appearance of oxidative stress over the 24 h that followed Isop treatment.…”