Uncoupling the coupled calcium and zinc dyshomeostasis in cardiac myocytes and mitochondria seen in aldosteronism

German Kamalov, Robert A. Ahokas, Wenyuan Zhao, Tieqiang Zhao, Atta U. Shahbaz, Patti L. Johnson, Syamal Bhattacharya, Yao Sun, Ivan Gerling, Karl Weber

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Intracellular [Ca]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 Ca overloading in cardiac myocytes and mitochondria is intrinsically coupled to simultaneous increased Zn entry serving as an antioxidant. Herein, we investigated whether Ca and Zn 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 ZnSO4 supplement; pyrrolidine dithiocarbamate (PDTC), a Zn ionophore; or ZnSO4 in combination with amlodipine (Amlod), a Ca channel blocker. We monitored and compared responses in cardiomyocyte free [Ca]i and [Zn]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]i coupled with [Zn]i and (2) 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 [Zn]i beyond that seen with ALDOST alone, whereas attenuating the rise in [Ca]i, which together served to reduce oxidative stress. Thus, a coupled dyshomeostasis of intracellular Ca and Zn was demonstrated in cardiac myocytes and mitochondria during 4-week ALDOST, where prooxidants overwhelm antioxidant defenses. This intrinsically coupled Ca and Zn dyshomeostasis could be uncoupled in favor of antioxidant defenses by selectively increasing free [Zn]i and/or reducing [Ca]i using cotreatment with ZnSO4 or PDTC alone or ZnSO4+Amlod in combination.

Original languageEnglish (US)
Pages (from-to)248-254
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume55
Issue number3
DOIs
StatePublished - Mar 1 2010

Fingerprint

Hyperaldosteronism
Cardiac Myocytes
Zinc
Aldosterone
Mitochondria
Calcium
Salts
Antioxidants
Amlodipine
8-epi-prostaglandin F2alpha
Oxidative Stress
Ionophores
Cicatrix
Cell Death
Biomarkers
pyrrolidine dithiocarbamic acid

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Uncoupling the coupled calcium and zinc dyshomeostasis in cardiac myocytes and mitochondria seen in aldosteronism. / Kamalov, German; Ahokas, Robert A.; Zhao, Wenyuan; Zhao, Tieqiang; Shahbaz, Atta U.; Johnson, Patti L.; Bhattacharya, Syamal; Sun, Yao; Gerling, Ivan; Weber, Karl.

In: Journal of Cardiovascular Pharmacology, Vol. 55, No. 3, 01.03.2010, p. 248-254.

Research output: Contribution to journalArticle

Kamalov, German ; Ahokas, Robert A. ; Zhao, Wenyuan ; Zhao, Tieqiang ; Shahbaz, Atta U. ; Johnson, Patti L. ; Bhattacharya, Syamal ; Sun, Yao ; Gerling, Ivan ; Weber, Karl. / Uncoupling the coupled calcium and zinc dyshomeostasis in cardiac myocytes and mitochondria seen in aldosteronism. In: Journal of Cardiovascular Pharmacology. 2010 ; Vol. 55, No. 3. pp. 248-254.
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