Temporal responses to intrinsically coupled calcium and zinc dyshomeostasis in cardiac myocytes and mitochondria during aldosteronism

Abstract

Intracellular Ca(2+) overloading, coupled to induction of oxidative stress, is present at 4-wk aldosterone/salt treatment (ALDOST). This prooxidant reaction in cardiac myocytes and mitochondria accounts for necrotic cell death and subsequent myocardial scarring. It is intrinsically linked to increased intracellular zinc concentration ([Zn(2+)](i)) serving as an antioxidant. Herein, we addressed the temporal responses in coupled Ca(2+) and Zn(2+) dyshomeostasis, reflecting the prooxidant-antioxidant equilibrium, by examining preclinical (week 1) and pathological (week 4) stages of ALDOST to determine whether endogenous antioxidant defenses would be ultimately overwhelmed to account for this delay in cardiac remodeling. We compared responses in cardiomyocyte free [Ca(2+)](i) and [Zn(2+)](i) and mitochondrial total [Ca(2+)](m) and [Zn(2+)](m), together with biomarkers of oxidative stress and antioxidant defenses, during 1- and 4-wk ALDOST. At week 1 and compared with controls, we found: 1) elevations in [Ca(2+)](i) and [Ca(2+)](m) were coupled with [Zn(2+)](i) and [Zn(2+)](m); 2) increased mitochondrial H(2)O(2) production, cardiomyocyte xanthine oxidase activity, and cardiac and mitochondrial 8-isoprostane levels, counterbalanced by increased activity of antioxidant proteins, enzymes, and the nonenzymatic antioxidants that can be considered as cumulative antioxidant capacity; some of these enzymes and proteins (e.g., metallothionein-1, Cu/Zn-superoxide, glutathione synthase) are regulated by metal-responsive transcription factor-1; and 3) although these augmented antioxidant defenses were sustained at week 4, they fell short in combating the persistent intracellular Ca(2+) overloading and marked rise in cardiac tissue 8-isoprostane and mitochondrial transition pore opening. Thus a coupled Ca(2+) and Zn(2+) dyshomeostasis occurs early during ALDOST in cardiac myocytes and mitochondria that regulate redox equilibrium until week 4 when ongoing intracellular Ca(2+) overloading and prooxidants overwhelm antioxidant defenses.

Coronary Microvascular Dysfunction Induced by Primary Hyperparathyroidism is Restored After Parathyroidectomy

“…1,5,17,22 Interestingly, in different tissues, PTH may exert an ionophoric effect, causing intracellular Ca 2ϩ overload and reactive oxygen species generation. 18,22,26 Indeed, impaired antioxidant defenses resulting from low intracellular zinc are often coupled to intracellular Ca 2ϩ overload and further worsen the redox imbalance, leading to severe cell injury and death. 26 In particular, PTH-mediated intracellular Ca 2ϩ accumulation, coupled to induction of excessive oxidative stress in cardiomyocytes and their mitochondria, has been linked to cell death and subsequent myocardial tissue repair.…”

“…18,22,26 Indeed, impaired antioxidant defenses resulting from low intracellular zinc are often coupled to intracellular Ca 2ϩ overload and further worsen the redox imbalance, leading to severe cell injury and death. 26 In particular, PTH-mediated intracellular Ca 2ϩ accumulation, coupled to induction of excessive oxidative stress in cardiomyocytes and their mitochondria, has been linked to cell death and subsequent myocardial tissue repair. In the long term, progressive parenchymal loss and reparative fibrosis compromise cardiac function and cause heart failure.…”

Remodelling of the heart and vessels in experimental hypertension: advances in protection

“…Simultaneously, hypozincaemia develops as a result of the stimulated urinary and faecal zinc excretion and zinc redistibution in the heart and other tissues. The intracellular zinc accumulation, associated with increased levels of antioxidant proteins and enzymes, can be considered to be a cumulative antioxidant capacity, which counteracts the burst of free radical formation induced by calcium overload [45]. This augmented antioxidant defence is, however, gradually overwhelmed by enhanced pro-oxidants [45], resulting in myocardial necrosis [46] and inflammatory cell activation with proinflammatory vascular phenotype, supporting the development of fibrosis [46,47].…”

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

“…In mitochondria, Ca 2+ overloading and oxidative stress lead to a nonphysiological opening of the mitochondria permeability transition pore, with the ensuing osmotic-based structural and functional degeneration of these organelles that triggers the downhill final common cell death pathway leading to cardiomyocyte necrosis and subsequent replacement fibrosis. 81 Interventions preventing cardiomyocyte necrosis A series of site-directed, sequential pharmacological interventions targeted along the cellular-molecular cascades to block downstream events leading to cardiomyocyte necrosis and myocardial scarring were conducted (see Figure 4). These observations collectively validated our hypothesis with regard to the pathological sequelae of events leading to this structural remodeling of myocardium in rats with chronic aldosteronism.…”

“…89 These salutary iterations in divalent cation composition corroborated well with the levels of 3-nitrotyrosine and 4-hydroxy-2-nonenal in cardiomyocytes, together with altered H 2 O 2 production, malondialdehyde and oxidized glutathione in the mitochondria that were co-incident with increased activities of Cu/Zn-SOD and glutathione peroxidase. 62,81,89 Furthermore, adaptive alterations in intracellular [Zn 2+ ] i were accompanied by the contemporaneous upregulation of MT-1, a Zn 2+ importer and exporter (Zip1 and ZnT-1, respectively) and metal-responsive transcription factor-1.…”