NOD1, a new player in cardiac function and calcium handling

Aims Inflammation is a significant contributor to cardiovascular disease and its complications; however, whether the myocardial inflammatory response is harmonized after cardiac injury remains to be determined. Some receptors of the innate immune system, including the nucleotide-binding oligomerization domain-like receptors (NLRs), play key roles in the host response after cardiac damage. Nucleotide-binding oligomerization domain containing 1 (NOD1), a member of the NLR family, is expressed in the heart, but its functional role has not been elucidated. We determine whether selective NOD1 activation modulates cardiac function and Ca2+ signalling. Methods and results Mice were treated for 3 days with the selective NOD1 agonist C12-iE-DAP (iE-DAP), and cardiac function and Ca2+ cycling were assessed. We found that iE-DAP treatment resulted in cardiac dysfunction, measured as a decrease in ejection fraction and fractional shortening. Cardiomyocytes isolated from iE-DAP-treated mice displayed a decrease in the L-type Ca2+ current, [Ca2+](i) transients and Ca2+ load, and decreased expression of phospho-phospholamban, sarcoplasmic reticulum-ATPase, and Na+-Ca2+ exchanger. Furthermore, iE-DAP prompted 'diastolic Ca2+ leak' in cardiomyocytes, resulting from increased Ca2+ spark frequency and RyR(2) over-phosphorylation. Importantly, these iE-DAP-induced changes in Ca2+ cycling were lost in NOD1(-/-) mice, indicating that iE-DAP exerts its actions through NOD1. Co-treatment of mice with iE-DAP and a selective inhibitor of NF-kappa B (BAY11-7082) prevented cardiac dysfunction and Ca2+ handling impairment induced by iE-DAP. Conclusion Our data provide the first evidence that NOD1 activation induces cardiac dysfunction associated with excitation-contraction coupling impairment through NF-kappa B activation and uncover a new pro-inflammatory player in the regulation of cardiovascular function.