TY - JOUR
T1 - Activation of α1-adrenergic receptor during Ca2+ pre-conditioning elicits strong protection against Ca2+ overload injury via protein kinase C signaling pathway
AU - Wang, Yigang
AU - Ashraf, Muhammad
N1 - Funding Information:
This study was supported in part by NIH research grants HL23597 and HL55678 from the National Heart, Lung and Blood Institute. The authors thank Atif Ashraf for technical assistance.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1998/11
Y1 - 1998/11
N2 - The objective was to test the hypothesis that transient activation of the α1-adrenergic receptor mimics the beneficial effects of Ca2+ preconditioning on the Ca2+ paradox (Ca2+ PD) injury in rat hearts, and that the protection is mediated by protein kinase C (PKC) signaling pathway. Langendorff-perfused rat hearts were subjected to the Ca2+ PD (10 min of Ca2+ depletion followed by 10 min of Ca2+ repletion). The effects of α1-adrenergic receptor activation and other interventions on functional, biochemical and pathological changes were assessed. In hearts pretreated with 50 μmol/l phenylephrine, left ventricular end-diastolic pressure and coronary flow were significantly preserved after Ca2+ PD; furthermore, peak loss of lactate dehydrogenase was significantly decreased while ATP was significantly preserved. A remarkable preservation of cell structure was observed in phenylephrine-treated hearts in contrast to non-treated Ca2+ PD hearts. However, pre-conditioning elicited by phenylephrine caused only a mild improvement in left ventricular developed pressure (LVDP) as opposed to its impressive recovery of left ventricular end-diastolic pressure (LVEDP), heart rate (HR), or coronary flow (CF). The salutary effects of phenylephrine on the Ca2+ PD injury were almost similar to those observed in hearts which underwent Ca2+ pre-conditioning (CPC) or were pretreated with 1-stearoyl-2-arachidonoyl-glycerol (SAG), a potent PKC activator. In phenylephrine pretreated hearts, PKC isoform-α was localized in the sarcolemma and nucleus, while PKC-δ and PKC-ε were localized in the cell membrane, and intercalated disk respectively. Prazosin, a specific α1-adrenergic receptor antagonist completely abolished the beneficial effects of phenylephrine on the Ca2+ PD and blocked translocation of PKC isoforms. In addition, prazosin (1 μmol/l) also reversed salutary effects of CPC. Moreover, the β-adrenergic antagonist, propranolol, had no effect on the protection provided by phenylephrine against the Ca2+ PD injury. This study suggests that the activation of the α1-adrenergic receptor confers protection against the lethal injury of the Ca2+ PD via PKC-mediated signaling pathways. The protection is shared by stimuli common with calcium pre-conditioning.
AB - The objective was to test the hypothesis that transient activation of the α1-adrenergic receptor mimics the beneficial effects of Ca2+ preconditioning on the Ca2+ paradox (Ca2+ PD) injury in rat hearts, and that the protection is mediated by protein kinase C (PKC) signaling pathway. Langendorff-perfused rat hearts were subjected to the Ca2+ PD (10 min of Ca2+ depletion followed by 10 min of Ca2+ repletion). The effects of α1-adrenergic receptor activation and other interventions on functional, biochemical and pathological changes were assessed. In hearts pretreated with 50 μmol/l phenylephrine, left ventricular end-diastolic pressure and coronary flow were significantly preserved after Ca2+ PD; furthermore, peak loss of lactate dehydrogenase was significantly decreased while ATP was significantly preserved. A remarkable preservation of cell structure was observed in phenylephrine-treated hearts in contrast to non-treated Ca2+ PD hearts. However, pre-conditioning elicited by phenylephrine caused only a mild improvement in left ventricular developed pressure (LVDP) as opposed to its impressive recovery of left ventricular end-diastolic pressure (LVEDP), heart rate (HR), or coronary flow (CF). The salutary effects of phenylephrine on the Ca2+ PD injury were almost similar to those observed in hearts which underwent Ca2+ pre-conditioning (CPC) or were pretreated with 1-stearoyl-2-arachidonoyl-glycerol (SAG), a potent PKC activator. In phenylephrine pretreated hearts, PKC isoform-α was localized in the sarcolemma and nucleus, while PKC-δ and PKC-ε were localized in the cell membrane, and intercalated disk respectively. Prazosin, a specific α1-adrenergic receptor antagonist completely abolished the beneficial effects of phenylephrine on the Ca2+ PD and blocked translocation of PKC isoforms. In addition, prazosin (1 μmol/l) also reversed salutary effects of CPC. Moreover, the β-adrenergic antagonist, propranolol, had no effect on the protection provided by phenylephrine against the Ca2+ PD injury. This study suggests that the activation of the α1-adrenergic receptor confers protection against the lethal injury of the Ca2+ PD via PKC-mediated signaling pathways. The protection is shared by stimuli common with calcium pre-conditioning.
KW - Ca paradox
KW - Ca pre-conditioning
KW - Phenylephrine
KW - Protein kinase C
KW - α-adrenergic receptor
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U2 - 10.1006/jmcc.1998.0802
DO - 10.1006/jmcc.1998.0802
M3 - Article
C2 - 9925377
AN - SCOPUS:0032194849
SN - 0022-2828
VL - 30
SP - 2423
EP - 2435
JO - Journal of molecular and cellular cardiology
JF - Journal of molecular and cellular cardiology
IS - 11
ER -