Ca ²⁺ /Calmodulin-Dependent Protein Kinase II and Protein Kinase A Differentially Regulate Sarcoplasmic Reticulum Ca ²⁺ Leak in Human Cardiac Pathology

Abstract

Background— Sarcoplasmic reticulum (SR) Ca 2+ leak through ryanodine receptor type 2 (RyR2) dysfunction is of major pathophysiological relevance in human heart failure (HF); however, mechanisms underlying progressive RyR2 dysregulation from cardiac hypertrophy to HF are still controversial. Methods and Results— We investigated healthy control myocardium (n=5) and myocardium from patients with compensated hypertrophy (n=25) and HF (n=32). In hypertrophy, Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) both phosphorylated RyR2 at levels that were not different from healthy myocardium. Accordingly, inhibitors of these kinases reduced the SR Ca 2+ leak. In HF, however, the SR Ca 2+ leak was nearly doubled compared with hypertrophy, which led to reduced systolic Ca 2+ transients, a depletion of SR Ca 2+ storage and elevated diastolic Ca 2+ levels. This was accompanied by a significantly increased CaMKII-dependent phosphorylation of RyR2. In contrast, PKA-dependent RyR2 phosphorylation was not increased in HF and was independent of previous β-blocker treatment. In HF, CaMKII inhibition but not inhibition of PKA yielded a reduction of the SR Ca 2+ leak. Moreover, PKA inhibition further reduced SR Ca 2+ load and systolic Ca 2+ transients. Conclusions— In human hypertrophy, both CaMKII and PKA functionally regulate RyR2 and may induce SR Ca 2+ leak. In the transition from hypertrophy to HF, the diastolic Ca 2+ leak increases and disturbed Ca 2+ cycling occurs. This is associated with an increase in CaMKII- but not PKA-dependent RyR2 phosphorylation. CaMKII inhibition may thus reflect a promising therapeutic target for the treatment of arrhythmias and contractile dysfunction.

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…Interestingly, despite enhanced expression of fetal genes in all phenotypes, p‐phospholamban, S16 was increased in the CR and MILD phenotypes and decreased in the MOD phenotype only. Thus, the MOD phenotype displayed features shown in other studies, where the transition from compensated hypertrophy to overt HF is characterized by increased calcium‐calmodulin‐dependent kinase II activity and decreased PKA phosphorylation of downstream targets leading to increased sarcoplasmic reticulum Ca 2+ leak, reduced sarcoplasmic reticulum Ca 2+ load, and therefore impaired systolic Ca 2+ transients 36. Similarly, the expression of NCX‐1, which is regulated by the mitogen‐activated protein kinases P38 and HDAC,41, 42 and mitochondrial apoptosis markers (Bax and BNIP3), which are regulated by the mitogen‐activated protein kinases JNK,12 were increased in the MOD phenotype only.…”

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

“…Furthermore, in the absence of extracellular calcium, CAP‐induced intracellular Ca 2+ increase was not observed (Figure 1D). Ca 2+ /CaMKII is activated by increased intracellular Ca 2+ concentration, and the CaMKII δ isoform found predominantly in the heart has been shown to play an essential role in cardiac hypertrophy 17. We explored whether CaMKII δ activity and phosphorylation were altered in TRPV1 activation–induced cardiac hypertrophy.…”

Genetic modulation of the SERCA activity does not affect the Ca2+ leak from the cardiac sarcoplasmic reticulum

“…In addition, the identification of an exchange protein that was directly activated by cAMP (Epac) further supported the importance of CaMKII-dependent phosphorylation through beta-adrenergic receptor stimulation in the heart [31-33]. Very recently, it has been reported that both CaMKII and PKA functionally regulate RyR but have differential roles in human cardiac pathology [34]. Therefore, abnormal Ca 2+ leak through the RyR may play a significant role in heart failure and may be another promising target of treatment.…”