The critical role of intracellular zinc in adenosine A2 receptor activation induced cardioprotection against reperfusion injury

Abstract

Exogenous zinc can protect cardiac cells from reperfusion injury, but the exact roles of endogenous zinc in the pathogenesis of reperfusion injury and in adenosine A 2 receptor activation-induced cardioprotection against reperfusion injury remain unknown. Adenosine A 1 /A 2 receptor agonist 5′-(N-ethylcarboxamido) adenosine (NECA) given at reperfusion reduced infarct size in isolated rat hearts subjected to 30 min ischemia followed by 2 h of reperfusion. This effect of NECA was partially but significantly blocked by the zinc chelator N,N,N′,N′-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), and ZnCl 2 given at reperfusion mimicked the effect of NECA by reducing infarct size. Total tissue zinc concentrations measured with inductively coupled plasma optical emission spectroscopy (ICPOES) were decreased upon reperfusion in rat hearts and this was reversed by NECA. NECA increased intracellular free zinc during reperfusion in the heart. Confocal imaging study showed a rapid increase in intracellular free zinc in isolated rat cardiomyocytes treated with NECA. Further experiments revealed that NECA increased total zinc levels upon reperfusion in mitochondria isolated from isolated hearts. NECA attenuated mitochondrial swelling upon reperfusion in isolated hearts and this was inhibited by TPEN. Similarly, NECA prevented the loss of mitochondrial membrane potential (ΔΨm) caused by oxidant stress in cardiomyocytes. Finally, both NECA and ZnCl 2 inhibited the mitochondrial metabolic activity. NECA-induced cardioprotection against reperfusion injury is mediated by intracellular zinc. NECA prevents reperfusion-induced zinc loss and relocates zinc to mitochondria. The inhibitory effects of zinc on both the mPTP opening and the mitochondrial metabolic activity may account for the cardioprotective effect of NECA.

Intracellular zinc release-activated ERK-dependent GSK-3β–p53 and Noxa–Mcl-1 signaling are both involved in cardiac ischemic-reperfusion injury

“…7,8 When a non-acetoxymethyl ester Zn 2 þ indicator, TSQ, is applied to the heart tissues, reperfusion induces a decrease, rather than an increase, in [Zn 2 þ ] i levels. 9,10 When a mixture of Zn 2 þ and the Zn 2 þ ionophore pyrithione is added to the reperfusion solution for 20-30 min, cardioprotection occurs, and two mechanisms have been suggested, namely preservation of protein kinase C (PKC) isoforms and inhibition of mitochondrial metabolism. 9,10 The molecular mechanism for the effect of the [Zn 2 þ ] i increase on cell survival is therefore still debatable.…”

Effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart

“…In the previous finding of Karagulova et al 2007, it shows that lipid activates the PKC which triggers the zinc release, so, we envisage the hyperlipidemia model for study. It was also studied that reperfusion induces cardiac zinc loss in isolated rat hearts, and prevention of zinc loss through the activation of adenosine A2 receptors leads to cardioprotection against reperfusion injury, indicating an important role of intracellular zinc in cardiac survival in the setting of reperfusion (McIntosh et al 2010). With this evidence, in our present study, zinc pyrithione significantly produces cardioprotection (decreased the release of LDH, CK-MB, collagen content, and myocardial infarct size) against attenuated cardioprotective effect of IPC in hyperlipidemic rat hearts, and administration of zinc chelator (TPEN) during reperfusion 2 min before zinc pyrithione perfusion attenuates the cardioprotection in hyperlipidemic rat hearts.…”

Stomatin-like Protein 2 Deficiency in T Cells Is Associated with Altered Mitochondrial Respiration and Defective CD4+ T Cell Responses

“…This is illustrated by defective activities of complexes I and II plus III of the electron transport chain and by increased respiration uncoupled to ATP production. The physiological relevance of a reduction of complex I activity is likely greater than what is measured because the assay commonly used to determine the activity of complex I only detects partial reaction of complex I (41)(42)(43). Defective complex I activity is considered the most common defect of the respiratory chain in humans (44) and causes a diverse set of diseases, including Leigh syndrome and renal tubular acidosis.…”