Activation of α1B-adrenoceptors alleviates ischemia/reperfusion injury by limitation of mitochondrial Ca2+ overload in cardiomyocytes

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Abstract

Objective: Activation of α1-adrenergic receptors (α1-ARs) mimics ischemic preconditioning (IP). However, the subtypes of α1-ARs involved and the protective mechanisms are not entirely clear. Here we tested the hypothesis that preservation of mitochondrial integrity, in particular, Ca2+ homeostasis via the epsilon isoform of protein kinase C (PKCε) and mitoKATP channels, may underlie the basis of α1B-AR-triggered cardioprotection. Methods: Indo-1 fluorescence in adult rat cardiomyocytes was used as an index of cytosolic ([Ca2+]c) or mitochondrial free Ca2+ concentration ([Ca2+]m), and cell shortening was measured simultaneously. Cells were subjected to 20 min of simulated ischemia followed by 30 min of reperfusion (I/R). Results: Activation of a1-ARs by phenylephrine significantly decreased I/R-induced [Ca2+]c and [Ca2+]m overload, mitochondrial cytochrome c release and ATP reduction, and improved Ca2+ transients and cell shortening. These protective effects were markedly inhibited by blockade of α1B-AR (chloroethylclonidine) but not α1A-AR (5′-methylurapidil) or α1D-AR (BMY 7378). Moreover, phenylephrine-afforded protection on the [Ca2+]m, [Ca2+]c, and cell shortening was lost when mitoKATP channels were inhibited with 5-hydroxydecanoate and PKCε with PKCε V1-2. However, PKCε V1-2 did not affect the mitoKATP channel opener diazoxide-induced protection on these parameters. Conclusions: These findings indicate that phenylephrine-induced protection on [Ca2+]m homeostasis is mediated by selective activation of α1B-AR via mitoKATP channel opening and PKCε activation. Mitochondrial function appears to be a determinant of [Ca2+]c and contractile function during I/R injury. © 2007 European Society of Cardiology.

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Gao, H., Chen, L., & Yang, H. T. (2007). Activation of α1B-adrenoceptors alleviates ischemia/reperfusion injury by limitation of mitochondrial Ca2+ overload in cardiomyocytes. Cardiovascular Research, 75(3), 584–595. https://doi.org/10.1016/j.cardiores.2007.04.008

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