Calcium and zinc dyshomeostasis during isoproterenol-induced acute stressor state

Abstract

Acute hyperadrenergic stressor states are accompanied by cation dyshomeostasis, together with the release of cardiac troponins predictive of necrosis. The signal-transducer-effector pathway accounting for this pathophysiological scenario remains unclear. We hypothesized that a dyshomeostasis of extra- and intracellular Ca2+ and Zn2+ occurs in rats in response to isoproterenol (Isop) including excessive intracellular Ca2+ accumulation (EICA) and mitochondrial [Ca2+]m-induced oxidative stress. Contemporaneously, the selective translocation of Ca2+ and Zn2+ to tissues contributes to their fallen plasma levels. Rats received a single subcutaneous injection of Isop (1 mg/kg body wt). Other groups of rats received pretreatment for 10 days with either carvedilol (C), a β-adrenergic receptor antagonist with mitochondrial Ca2+ uniporter-inhibiting properties, or quercetin (Q), a flavonoid with mitochondrial-targeted antioxidant properties, before Isop. We monitored temporal responses in the following: [Ca2+] and [Zn2+] in plasma, left ventricular (LV) apex, equator and base, skeletal muscle, liver, spleen, and peripheral blood mononuclear cells (PBMC), indices of oxidative stress and antioxidant defenses, mitochondrial permeability transition pore (mPTP) opening, and myocardial fibrosis. We found ionized hypocalcemia and hypozincemia attributable to their tissue translocation and also a heterogeneous distribution of these cations among tissues with a preferential Ca2+ accumulation in the LV apex, muscle, and PBMC, whereas Zn2+ declined except in liver, where it increased corresponding with upregulation of metallothionein, a Zn2+-binding protein. EICA was associated with a simultaneous increase in tissue 8-isoprostane and increased [Ca2+]m accompanied by a rise in H2O2 generation, mPTP opening, and scarring, each of which were prevented by either C or Q. Thus excessive [Ca2+]m, coupled with the induction of oxidative stress and increased mPTP opening, suggests that this signal-transducer-effector pathway is responsible for Isop-induced cardiomyocyte necrosis at the LV apex.

Zinc and the Prooxidant Heart Failure Phenotype

“…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).…”

“…Other factors contributing to hypozincemia in CHF include: i ) urinary Zn 2+ losses associated with ACE inhibitor treatment (7); ii ) reduced dietary Zn 2+ intake and/or impaired small intestinal Zn 2+ absorption (8); and iii ) Zn 2+ translocation for storage within the liver, muscle and bone with subsequent release for purposes of tissue repair, e.g., during recurrent episodes of myocyte necrosis (21, 52). Resultant Zn 2+ deficiency contributes to the systemic illness of CHF by causing: i ) prooxidant phenotype with oxidative stress-induced damage to cardiomyocytes, tissue DNA, proteins and lipids (57); and ii ) an immunostimulatory state with activated immune cells elaborating proinflammatory cytokines.…”

Zinc-Permeable Ion Channels: Effects on Intracellular Zinc Dynamics and Potential Physiological/Pathophysiological Significance

“…Insults that result from traumatic brain injury, brain ischemia and epilepsy, for example, contribute to excessive Zn 2+ levels [34-36]. Dysfunctional Zn 2+ regulation in the mitochondria, leads to a disruption of cell metabolism [37-39]. The energy-generating mitochondrial oxidation-reduction reaction, on the other hand, requires the presence of intracellular Zn 2+ ; mitochondrial complexes are not functional when Zn 2+ is chelated, essentially abating ATP generation [40].…”

Mitochondria play a central role in nonischemic cardiomyocyte necrosis: common to acute and chronic stressor states

“…The Fleckenstein hypothesis of nonischemic cardiomyocyte necrosis has recently been broadened into a central mitochondriocentric signal-transducer-effector (MSTE) pathway and found to be common to both acute and chronic stressor states [74,41]. As Fleckenstein envisaged, the signal for this pathway includes catecholamine- or PTH-mediated intracellular Ca 2+ overloading (see Figure 1).…”