Journal of Biological Chemistry
Volume 282, Issue 15, 13 April 2007, Pages 11397-11409
Journal home page for Journal of Biological Chemistry

Molecular Basis of Cell and Developmental Biology
Acute β-Adrenergic Overload Produces Myocyte Damage through Calcium Leakage from the Ryanodine Receptor 2 but Spares Cardiac Stem Cells*

https://doi.org/10.1074/jbc.M607391200Get rights and content
Under a Creative Commons license
open access

A hyperadrenergic state is a seminal aspect of chronic heart failure. Also, “Takotsubo stress cardiomyopathy,” is associated with increased plasma catecholamine levels. The mechanisms of myocyte damage secondary to excess catecholamine exposure as well as the consequence of this neurohumoral burst on cardiac stem cells (CSCs) are unknown. Cardiomyocytes and CSCs were exposed to high doses of isoproterenol (ISO), in vivo and in vitro. Male Wistar rats received a single injection of ISO (5 mg kg-1) and were sacrificed 1, 3, and 6 days later. In comparison with controls, LV function was impaired in rats 1 day after ISO and started to improve at 3 days. The fraction of dead myocytes peaked 1 day after ISO and decreased thereafter. ISO administration resulted in significant ryanodine receptor 2 (RyR2) hyperphosphorylation and RyR2-calstabin dissociation. JTV519, a RyR2 stabilizer, prevented the ISO-induced death of adult myocytes in vitro. In contrast, CSCs were resistant to the acute neurohumoral overload. Indeed, CSCs expressed a decreased and inverted complement of β12-adrenoreceptors and absence of RyR2, which may explain their survival to ISO insult. Thus, a single injection of ISO causes diffuse myocyte death through Ca2+ leakage secondary to the acutely dysfunctional RyR2. CSCs are resistant to the noxious effects of an acute hyperadrenergic state and through their activation participate in the response to the ISO-induced myocardial injury. The latter could contribute to the ability of the myocardium to rapidly recover from acute hyperadrenergic damage.

Cited by (0)

*

This work was supported by British Heart Foundation Ph.D. Studentship FS/2001028/12895 (to G. M. E.), the Louis B. Meyer Foundation, a fellowship award from the American Heart Association (to G. M. E.), and Italian Health Minister Grant PRIN2005 2005060509-003. The Mount Sinai School of Medicine-Microscopy Shared Resource Facility was supported with funding from NCI, National Institutes of Health (NIH), shared resources Grant 5R24 CA095823-04, National Science Foundation Major Research Instrumentation Grant (DBI-9724504), and NIH shared instrumentation grant 1 S10 RR0 9145-01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

The first two authors equally contributed to the present study.