Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Abstract

Aberrant intracellular Ca 2+ regulation is believed to contribute to the development of cardiomyopathy in Duchenne muscular dystrophy. Here, we tested whether inhibition of protein kinase A (PKA) phosphorylation of ryanodine receptor type 2 (RyR2) prevents dystrophic cardiomyopathy by reducing SR Ca 2+ leak in the mdx mouse model of Duchenne muscular dystrophy. mdx mice were crossed with RyR2-S2808A mice, in which PKA phosphorylation site S2808 on RyR2 is inactivated by alanine substitution. Compared with mdx mice that developed age-dependent heart failure, mdx-S2808A mice exhibited improved fractional shortening and reduced cardiac dilation. Whereas application of isoproterenol severely depressed cardiac contractility and caused 95% mortality in mdx mice, contractility was preserved with only 19% mortality in mdx-S2808A mice. SR Ca 2+ leak was greater in ventricular myocytes from mdx than mdx-S2808A mice. Myocytes from mdx mice had a higher incidence of isoproterenol-induced diastolic Ca 2+ release events than myocytes from mdx-S2808A mice. Thus, inhibition of PKA phosphorylation of RyR2 reduced SR Ca 2+ leak and attenuated cardiomyopathy in mdx mice, suggesting that enhanced PKA phosphorylation of RyR2 at S2808 contributes to abnormal Ca 2+ homeostasis associated with dystrophic cardiomyopathy.calcium | cardiomyopathy | dystrophin | ryanodine receptor | sarcoplasmic reticulum

Genetic Deletion of Rnd3/RhoE Results in Mouse Heart Calcium Leakage Through Upregulation of Protein Kinase A Signaling

“…29, 30 The PKA-mediated destabilization of the RyR2 channels was demonstrated in several mouse models as well. 21-23, 31-33 Overexpression of PKA catalytic domain in mouse heart tissues was sufficient to lead to dilated cardiomyopathy and sudden cardiac death. 22 Genetic inhibition of PKA-mediated RyR2 phosphorylation attenuated RyR2 leakage, 23 and prevented heart failure induced by chronic stimulation of β-adrenergic signaling.…”

“…21-23, 31-33 Overexpression of PKA catalytic domain in mouse heart tissues was sufficient to lead to dilated cardiomyopathy and sudden cardiac death. 22 Genetic inhibition of PKA-mediated RyR2 phosphorylation attenuated RyR2 leakage, 23 and prevented heart failure induced by chronic stimulation of β-adrenergic signaling. 34 We would like to indicate that whether PKA-mediated RyR2 phosphorylation at serine 2808 (S2808) directly leads to RyR2 dysfunction remains controversial.…”

Ethanol Extract ofLycopus lucidusElicits Positive Inotropic Effect Via Activation of Ca2+Entry and Ca2+Release in Beating Rabbit Atria

“…19 RyR, as a SR Ca 2 + release channel, is an essential component of ECC in cardiac contractility and is modulated by several factors such as Ca 2 + , Mg 2 + , and protein kinase A (PKA). 20,21 Further, phospholamban is a phosphoprotein modulating Ca 2 + -ATPase 2a through which ELT (0.3 mg/mL), n = 6; propranolol (1 lM) + ELT (0.3 mg/mL), n = 4; propranolol control, n = 3. *P < .001 vs. control period; # P < .01 vs. the values before the addition of ELT; ++ P < .001 vs. control period; $ P < .001 vs. control group; & P < .001 vs. control group.…”

SERCA2a Gene Therapy Can Improve Symptomatic Heart Failure in δ-Sarcoglycan-Deficient Animals

“…However, the membrane instability also allows increased entry of calcium via nonspecific channels and mitochondrial disorganization (Fraysse et al, 2010). Ample evidence suggests that abnormal elevation of cytosolic calcium may play a central role in the pathogenesis of heart disease (Dunn and Radda, 1991;Alloatti et al, 1995;Williams and Allen, 2007;Fauconnier et al, 2010;Sarma et al, 2010).…”