Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells

A hyperadrenergic state is a seminal aspect of chronic heartfailure. Also, “Takotsubo stress cardiomyopathy,” is associatedwith increased plasma catecholamine levels. The mechanisms ofmyocyte damage secondary to excess catecholamine exposure aswell as the consequence of this neurohumoral burst on cardiacstem cells (CSCs) are unknown. Cardiomyocytes and CSCs wereexposed to high doses of isoproterenol (ISO), in vivo and in vitro.Male Wistar rats received a single injection of ISO (5 mg kg1)and were sacrificed 1, 3, and 6 days later. In comparison withcontrols, LV function was impaired in rats 1 day after ISO andstarted to improve at 3 days. The fraction of dead myocytespeaked 1 day after ISO and decreased thereafter. ISO administrationresulted in significant ryanodine receptor 2 (RyR2)hyperphosphorylation and RyR2-calstabin dissociation.JTV519, a RyR2 stabilizer, prevented the ISO-induced death ofadult myocytes in vitro. In contrast, CSCs were resistant to theacute neurohumoral overload. Indeed, CSCs expressed adecreased and inverted complement of 1/2-adrenoreceptorsand absence of RyR2, which may explain their survival to ISOinsult. Thus, a single injection of ISO causes diffuse myocytedeath through Ca2 leakage secondary to the acutely dysfunctionalRyR2. CSCs are resistant to the noxious effects of an acutehyperadrenergic state and through their activation participatein the response to the ISO-induced myocardial injury. The lattercould contribute to the ability of the myocardium to rapidlyrecover from acute hyperadrenergic damage.