Molecular determinants of altered contractility in heart failure

Heart failure remains a leading cause of mortality in the Western world. An important hallmark of heart failure is reduced myocardial contractility. Alterations in intracellular Ca2+ handling play a major role in the pathophysiology of these contractile abnormalities. Several defects in the excitation-contraction (EC) coupling system have been identified in patients with heart failure. Alterations in the density and function of proteins relevant for EC coupling have been reported. Chronic stimulation of the beta-adrenergic signaling pathway leads to protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2), which dissociates FKBP12.6 from RyR2, thereby altering channel gating and promoting diastolic sarcoplasmic reticulum (SR) Ca2+ release. This may deplete the SR Ca2+ stores, which may reduce myocardial contractility. Clinical studies have demonstrated that beta-adrenergic receptor blockers reduce morbidity and mortality in all grades of congestive heart failure. Our experimental data indicate that beta-blockers reverse RyR2 hyperphosphorylation and normalize channel gating, which is associated with increased contractility in heart failure. In conclusion, chronic hyperactivity of the beta-adrenergic signaling pathway impairs intracellular Ca2+ handling, which leads to reduced contractility in patients with heart failure.     

A vaccine against Helicobacter pylori: towards understanding the mechanism of protection

Helicobacter pylori infection remains a significant global public health problem. Vaccine development against this infection appears to be feasible but has not yet delivered its promise in clinical trials. Efforts to improve current vaccination strategies would greatly benefit from a better molecular understanding of the mechanism of protection. Here, we review recent developments in this field.     

Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice

Atrial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca²⁺ handling. Diastolic Ca²⁺ release from the sarcoplasmic reticulum via “leaky” ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2^R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice. Rapid atrial pacing resulted in increased Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2, while both pharmacologic and genetic inhibition of CaMKII prevented AF inducibility in Ryr2^R176Q/+ mice. This result suggests that AF requires both an arrhythmogenic substrate (e.g., RyR2 mutation) and enhanced CaMKII activity. Increased CaMKII phosphorylation of RyR2 was observed in atrial biopsies from mice with atrial enlargement and spontaneous AF, goats with lone AF, and patients with chronic AF. Genetic inhibition of CaMKII phosphorylation of RyR2 in Ryr2^S2814A knockin mice reduced AF inducibility in a vagotonic AF model. Together, these findings suggest that increased RyR2-dependent Ca²⁺ leakage due to enhanced CaMKII activity is an important downstream effect of CaMKII in individuals susceptible to AF induction.