Coupled calcium and zinc dyshomeostasis and oxidative stress in cardiac myocytes and mitochondria of rats with chronic aldosteronism

German Kamalov, Prajwal A. Deshmukh, Narina Y. Baburyan, Malay S. Gandhi, Patti L. Johnson, Robert A. Ahokas, Syamal Bhattacharya, Yao Sun, Ivan Gerling, Karl Weber

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Abstract

A dyshomeostasis of extra- and intracellular Ca and Zn occurs in rats receiving chronic aldosterone/salt treatment (ALDOST). Herein, we hypothesized that the dyshomeostasis of intracellular Ca and Zn is intrinsically coupled that alters the redox state of cardiac myocytes and mitochondria, with Ca serving as a pro-oxidant and Zn as an antioxidant. Toward this end, we harvested hearts from rats receiving 4 weeks of ALDOST alone or cotreatment with either spironolactone (Spiro), an aldosterone receptor antagonist, or amlodipine (Amlod), an L-type Ca channel blocker, and from age/sex-matched untreated controls. In each group, we monitored cardiomyocyte [Ca]i and [Zn]i and mitochondrial [Ca]m and [Zn]m; biomarkers of oxidative stress and antioxidant defenses; expression of Zn transporters, Zip1 and ZnT-1; metallothionein-1, a Zn-binding protein; and metal response element transcription factor-1, a [Zn]i sensor and regulator of antioxidant defenses. Compared with controls, at 4-week ALDOST, we found the following: (a) increased [Ca]i and [Zn]i, together with increased [Ca]m and [Zn]m, each of which could be prevented by Spiro and attenuated with Amlod; (b) increased levels of 3-nitrotyrosine and 4-hydroxy-2-nonenal in cardiomyocytes, together with increased H2O2 production, malondialdehyde, and oxidized glutathione in mitochondria that were coincident with increased activities of Cu/Zn superoxide dismutase and glutathione peroxidase; and (c) increased expression of metallothionein-1, Zip1 and ZnT-1, and metal response element transcription factor-1, attenuated by Spiro. Thus, an intrinsically coupled dyshomeostasis of intracellular Ca and Zn occurs in cardiac myocytes and mitochondria in rats receiving ALDOST, where it serves to alter their redox state through a respective induction of oxidative stress and generation of antioxidant defenses. The importance of therapeutic strategies that can uncouple these two divalent cations and modulate their ratio in favor of sustained antioxidant defenses is therefore suggested.

Original languageEnglish (US)
Pages (from-to)414-423
Number of pages10
JournalJournal of Cardiovascular Pharmacology
Volume53
Issue number5
DOIs
StatePublished - May 1 2009

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Hyperaldosteronism
Cardiac Myocytes
Zinc
Mitochondria
Oxidative Stress
Calcium
Aldosterone
Antioxidants
Salts
Amlodipine
Spironolactone
Metallothionein
Response Elements
Oxidation-Reduction
Transcription Factors
Metals
Mineralocorticoid Receptor Antagonists
Glutathione Disulfide
Divalent Cations
Glutathione Peroxidase

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Coupled calcium and zinc dyshomeostasis and oxidative stress in cardiac myocytes and mitochondria of rats with chronic aldosteronism. / Kamalov, German; Deshmukh, Prajwal A.; Baburyan, Narina Y.; Gandhi, Malay S.; Johnson, Patti L.; Ahokas, Robert A.; Bhattacharya, Syamal; Sun, Yao; Gerling, Ivan; Weber, Karl.

In: Journal of Cardiovascular Pharmacology, Vol. 53, No. 5, 01.05.2009, p. 414-423.

Research output: Contribution to journalArticle

Kamalov, German ; Deshmukh, Prajwal A. ; Baburyan, Narina Y. ; Gandhi, Malay S. ; Johnson, Patti L. ; Ahokas, Robert A. ; Bhattacharya, Syamal ; Sun, Yao ; Gerling, Ivan ; Weber, Karl. / Coupled calcium and zinc dyshomeostasis and oxidative stress in cardiac myocytes and mitochondria of rats with chronic aldosteronism. In: Journal of Cardiovascular Pharmacology. 2009 ; Vol. 53, No. 5. pp. 414-423.
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AU - Gandhi, Malay S.

AU - Johnson, Patti L.

AU - Ahokas, Robert A.

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