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

Abstract

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 ␤ 1 /␤ 2 -adrenoreceptors and absence of RyR2, which may explain their survival to ISO insult. Thus, a single injection of ISO causes diffuse myocyte death through Ca 2؉ 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.

CPU86017, a berberine derivative, attenuates cardiac failure through normalizing calcium leakage and downregulated phospholamban and exerting antioxidant activity

“…Changes in cardiac function by the two steps coincided with changes in biomarkers including RyR2 and its modulator FKBP12.6, as well as SERCA2a and its modulator PLB. This is in line with other published findings on aggravating cardiac failure by ISO injection [5,[29][30][31] .…”

“…The process of calcium homeostasis, however, is critically impaired due to hyperphosphorylation of protein kinase A (PKA) [4] . PKA hyperphosphorylated exists in a hyperadrenergic state [5] elicited by isoproterenol (ISO) treatment, resulting in both arrhythmogenesis and HF [1] . Impaired calcium homeostasis may not be due solely to the effects of the RyR2-FKBP12.6 complex and the impact of hyperphosphorylation of PKA.…”

“…CPVT is triggered by physical exercise, and is related to leakiness of RyR2 channels and defective/downregulated FKBP12.6 [20] . This condition can also be produced by ISO treatment [5] . This is likely due to an activated endothelin-1 (ET-1) system and oxidative stress [8] .…”

Nuclear Calcium/Calmodulin-dependent Protein Kinase II Signaling Enhances Cardiac Progenitor Cell Survival and Cardiac Lineage Commitment

“…CPCs express Ca 2ϩ receptors and pumps, however, expression of the Ryanodine receptors and ␤1-AR are not present in CPCs indicating that these cells hold a primitive molecular cardiac signature (39). Related to our study, CPCs transfected with a siRNA targeting HDAC4, and therefore inhibiting the repression of growth genes, increased differentiation of CPCs in vivo supporting myocardial regeneration (29).…”

“…Inositol-1,4,5-triphosphate (IP3) receptors on the sarcoplasmic reticulum induce spontaneous Ca 2ϩ oscillations in mouse and human CPCs (37,38). CPCs are validated to not only express IP3 receptors, but also purinergic G protein-coupled receptors (P2Y) and SERCA2, which are functionally stimulated and activated after introduction of Ca 2ϩ and/or ATP (38,39). Furthermore, IP3 receptors promote an influx of Ca 2ϩ in the nucleus activating CaMKII/MEF2 and cellular growth (40).…”