Document Detail


{beta}1-Adrenergic receptor activation induces mouse cardiac myocyte death through both L-type calcium channel-dependent and -independent pathways.
MedLine Citation:
PMID:  20495143     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Wei Wang; Hongyu Zhang; Hui Gao; Hajime Kubo; Remus M Berretta; Xiongwen Chen; Steven R Houser
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-05-21
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-30     Completed Date:  2010-08-30     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H322-31     Citation Subset:  IM    
Affiliation:
Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-1 Receptor Agonists*
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists / pharmacology*
Animals
Antioxidants / pharmacology
Calcium Channel Blockers / pharmacology
Calcium Channels, L-Type / drug effects*,  genetics,  metabolism
Calcium Signaling / drug effects*
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors,  metabolism
Caspase Inhibitors
Caspases / metabolism
Cell Survival / drug effects
Cells, Cultured
Cysteine Proteinase Inhibitors / pharmacology
Isoproterenol / pharmacology*
Membrane Potentials
Mice
Mice, Transgenic
Myocardial Contraction / drug effects*
Myocytes, Cardiac / drug effects*,  metabolism,  pathology
Necrosis
Protein Subunits
Reactive Oxygen Species / metabolism
Receptors, Adrenergic, beta-1 / metabolism
Receptors, Adrenergic, beta-2 / metabolism
Sarcoplasmic Reticulum / drug effects,  metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors,  metabolism
Sodium-Calcium Exchanger / antagonists & inhibitors*,  metabolism
Time Factors
Grant Support
ID/Acronym/Agency:
HL033921/HL/NHLBI NIH HHS; HL088243/HL/NHLBI NIH HHS; HL089312/HL/NHLBI NIH HHS; HL091799/HL/NHLBI NIH HHS; R01 HL088243-01/HL/NHLBI NIH HHS; R01 HL088243-02/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adrb1 protein, mouse; 0/Adrenergic beta-1 Receptor Agonists; 0/Adrenergic beta-2 Receptor Agonists; 0/Adrenergic beta-Agonists; 0/Antioxidants; 0/Calcium Channel Blockers; 0/Calcium Channels, L-Type; 0/Caspase Inhibitors; 0/Cysteine Proteinase Inhibitors; 0/Protein Subunits; 0/Reactive Oxygen Species; 0/Receptors, Adrenergic, beta-1; 0/Receptors, Adrenergic, beta-2; 0/Sodium-Calcium Exchanger; 7683-59-2/Isoproterenol; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinase Type 2; EC 3.4.22.-/Caspases; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases
Comments/Corrections

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