Zinc dyshomeostasis in rats with aldosteronism. Response to spironolactone

Thomas, M.; Vidal, A.; Bhattacharya, Syamal K.; Ahokas, Robert A.; Sun, Yao; Gerling, Ivan; Weber, Karl T.

doi:10.1152/ajpheart.00200.2007

Cited by 34 publications

(48 citation statements)

References 54 publications

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“…The degree of hypozincemia correlates with the severity of injury. Zn 2+ is translocated to sites of injury and to liver for storage, facilitated by upregulated expression of MT1 (6, 21). In response to tissue injury involving heart, kidney or lung, where circulating Zn 2+ levels decline while Zn 2+ is redistributed to injured tissues based, in part, on MT1 upregulation, and where tissue Cu/Zn-SOD expression and activity are increased (48–51).…”

Section: Zn2+ Dyshomeostasis In Stressor Statesmentioning

confidence: 99%

“…In response to tissue injury involving heart, kidney or lung, where circulating Zn 2+ levels decline while Zn 2+ is redistributed to injured tissues based, in part, on MT1 upregulation, and where tissue Cu/Zn-SOD expression and activity are increased (48–51). At the site of injury, Zn 2+ participates in wound healing, including: initiation of gene transcription and protein synthesis; immune cell replication and functions; and activation of metalloproteinases (6, 52). The hypokalemia and ionized hypocalcemia and hypomagnesemia seen on admission with acute hyperadrenergic states is based on catecholamine-mediated translocation of these cations to skeletal muscle and adipose tissue, respectively (reviewed in 53).…”

Section: Zn2+ Dyshomeostasis In Stressor Statesmentioning

confidence: 99%

“…The most relevant underlying pathophysiologic mechanism for hypozincemia is renin-angiotensin-aldosterone system (RAAS) activation with renin-dependent aldosteronism, where a marked increase in fecal and urinary Zn excretion occurs and which can be blocked by an aldosterone receptor antagonist (6). Other factors contributing to hypozincemia in CHF include urinary Zn 2+ losses associated with angiotensin-converting enzyme (ACE) inhibitor treatment (7) and reduced dietary Zn 2+ intake and/or impaired small intestine absorption of Zn 2+ (8).…”

Section: Introductionmentioning

confidence: 99%

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Zinc and the Prooxidant Heart Failure Phenotype

Efeovbokhan

Bhattacharya

Ahokas

et al. 2014

Journal of Cardiovascular Pharmacology

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Neurohormonal activation with attendant aldosteronism contributes to the clinical appearance of congestive heart failure (CHF). Aldosteronism is intrinsically coupled to Zn2+ and Ca2+ dyshomeostasis, in which consequent hypozincemia compromises Zn2+ homeostasis and Zn2+-based antioxidant defenses that contribute to the CHF prooxidant phenotype. Ionized hypocalcemia leads to secondary hyperparathyroidism with parathyroid hormone-mediated Ca2+ overloading of diverse cells, including cardiomyocytes. When mitochondrial Ca2+ overload exceeds a threshold, myocyte necrosis follows. The reciprocal regulation involving cytosolic free [Zn2+]i as antioxidant and [Ca2+]i as prooxidant that can be uncoupled in favor of Zn2+-based antioxidant defenses. Increased [Zn2+]i acts as a multifaceted antioxidant by: i) inhibiting Ca2+ entry via L-type channels and hence cardioprotectant from the Ca2+-driven mitochondriocentric signal-transducer-effector pathway to nonischemic necrosis; ii) serving as catalytic regulator of Cu/Zn-superoxide dismutase; and iii) activating its cytosolic sensor, metal-responsive transcription factor that regulates the expression of relevant antioxidant defense genes. Albeit present in subnanomolar range, increased cytosolic free [Zn2+]i enhances antioxidant capacity that confers cardioprotection. It can be achieved exogenously by ZnSO4 supplementation or endogenously, using a β3 receptor agonist, (e.g., nebivolol) that enhances NO generation to release inactive cytosolic Zn2+ bound to metallothionein. By recognizing the pathophysiologic relevance of Zn2+ dyshomeostasis in the prooxidant CHF phenotype and by exploiting the pharmacophysiologic potential of [Zn2+]i as antioxidant, vulnerable cardiomyocytes under assault from neurohormonal activation can be protected and the myocardium spared from adverse structural remodeling.

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Section: Zn2+ Dyshomeostasis In Stressor Statesmentioning

confidence: 99%

Section: Zn2+ Dyshomeostasis In Stressor Statesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Zinc and the Prooxidant Heart Failure Phenotype

Efeovbokhan

Bhattacharya

Ahokas

et al. 2014

Journal of Cardiovascular Pharmacology

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“…Chronic inappropriate excess of aldosterone is accompanied by increased urinary and fecal excretory Zn 2+ losses, hypozincemia, and a fall in plasma Cu/Zn-SOD activity [70]. The hyperzincuria seen with ALDOST is related to urinary acidification, which contributes to the consequent metabolic alkalosis of aldosteronism [59].…”

Section: Cellular and Molecular Pathways Leading To Cardiomyocyte Necmentioning

confidence: 99%

“…The hyperzincuria seen with ALDOST is related to urinary acidification, which contributes to the consequent metabolic alkalosis of aldosteronism [59]. Also contributory to hypozincemia is a coordinated selective translocation of Zn 2+ to the sites of tissue injury, facilitated by corresponding upregulation of a Zn 2+ -binding protein, metallothionein (MT)-1 in targeted tissues [59, 70]. …”

Section: Cellular and Molecular Pathways Leading To Cardiomyocyte Necmentioning

confidence: 99%

Cellular and molecular pathways to myocardial necrosis and replacement fibrosis

et al. 2010

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Fibrosis is a fundamental component of the adverse structural remodeling of myocardium present in the failing heart. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but not without adverse functional consequences. The extensive nature of this microscopic scarring suggests cardiomyocyte necrosis is widespread and the loss of these contractile elements, combined with fibrous tissue deposition in the form of a stiff in-series and in-parallel elastic elements, contributes to the progressive failure of this normally efficient muscular pump. Cellular and molecular studies into the signaltransducer-effector pathway involved in cardiomyocyte necrosis have identified the crucial pathogenic role of intracellular Ca 2+ overloading and subsequent induction of oxidative stress, Correspondence to: Karl T. Weber, KTWeber@uthsc.edu. NIH Public Access Author ManuscriptHeart Fail Rev. Author manuscript; available in PMC 2012 January 1. Published in final edited form as:Heart Fail Rev. 2011 January ; 16(1): 23-34. doi:10.1007/s10741-010-9169-3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript predominantly confined within its mitochondria, to be followed by the opening of the mitochondrial permeability transition pore that leads to the destruction of these organelles and cells. It is now further recognized that Ca 2+ overloading of cardiac myocytes and mitochondria serves as a prooxidant and which is counterbalanced by an intrinsically coupled Zn 2+ entry serving as antioxidant. The prospect of raising antioxidant defenses by increasing intracellular Zn 2+ with adjuvant nutriceuticals can, therefore, be preferentially exploited to uncouple this intrinsically coupled Ca 2+ -Zn 2+ dyshomeostasis. Hence, novel yet simple cardioprotective strategies may be at hand that deserve to be further explored.

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