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Am J Physiol Heart Circ Physiol. 2010 Aug;299(2):H322-31. doi: 10.1152/ajpheart.00392.2010. Epub 2010 May 21.

{beta}1-Adrenergic receptor activation induces mouse cardiac myocyte death through both L-type calcium channel-dependent and -independent pathways.

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  • 1Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.

Abstract

Cardiac diseases persistently increase the contractility demands of cardiac myocytes, which require activation of the sympathetic nervous system and subsequent increases in myocyte Ca(2+) transients. Persistent exposure to sympathetic and/or Ca(2+) stress is associated with myocyte death. This study examined the respective roles of persistent beta-adrenergic receptor (beta-AR) agonist exposure and high Ca(2+) concentration in myocyte death. Ventricular myocytes (VMs) were isolated from transgenic (TG) mice with cardiac-specific and inducible expression of the beta(2a)-subunit of the L-type Ca(2+) channel (LTCC). VMs were cultured, and the rate of myocyte death was measured in the presence of isoproterenol (ISO), other modulators of Ca(2+) handling and the beta-adrenergic system, and inhibitors of caspases and reactive oxygen species generation. The rate of myocyte death was greater in TG vs. wild-type myocytes and accelerated by ISO in both groups, although ISO did not increase LTCC current (I(Ca-L)) in TG-VMs. Nifedipine, an LTCC antagonist, only partially prevented myocyte death. These results suggest both LTCC-dependent and -independent mechanisms in ISO induced myocyte death. ISO increased the contractility of wild type and TG-VMs by enhancing sarcoplasmic reticulum function and inhibiting sarco(endo)plasmic reticulum Ca(2+)-ATPase, Na(+)/Ca(2+) exchanger, and CaMKII partially protected myocyte from death induced by both Ca(2+) and ISO. Caspase and reactive oxygen species inhibitors did not, but beta(2)-AR activation did, reduce myocyte death induced by enhanced I(Ca-L) and ISO stimulation. Our results suggest that catecholamines induce myocyte necrosis primarily through beta(1)-AR-mediated increases in I(Ca-L), but other mechanisms are also involved in rodents.

PMID:
20495143
[PubMed - indexed for MEDLINE]
PMCID:
PMC2930381
Free PMC Article

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