Acute β-Adrenergic Overload Produces Myocyte Damage through Calcium Leakage from the Ryanodine Receptor 2 but Spares Cardiac Stem Cells

Georgina M Ellison, Daniele Torella, Ioannis Karakikes, Saranya Purushothaman, Antonio Curcio, Cosimo Gasparri, Ciro Indolfi, N Tim Cable, David F Goldspink, Bernardo Nadal-Ginard

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    145 Citations (Scopus)


    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 beta1/beta2-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.
    Original languageEnglish
    Pages (from-to)11397-409
    Number of pages13
    JournalJournal of Biological Chemistry
    Issue number15
    Publication statusPublished - 13 Apr 2007


    • Animals
    • Heart Failure
    • Calcium
    • Muscle Cells
    • Isoproterenol
    • Rats
    • Receptors, Adrenergic, beta
    • Phosphorylation
    • Cell Death
    • Rats, Wistar
    • Ryanodine Receptor Calcium Release Channel
    • Stem Cells
    • Time Factors
    • Male


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