| First Author | Delgado C | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 106 |
| Issue | 3 | Pages | 375-86 |
| PubMed ID | 25824149 | Mgi Jnum | J:251253 |
| Mgi Id | MGI:6106337 | Doi | 10.1093/cvr/cvv118 |
| Citation | Delgado C, et al. (2015) NOD1, a new player in cardiac function and calcium handling. Cardiovasc Res 106(3):375-86 |
| abstractText | 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 Ca(2+) signalling. METHODS AND RESULTS: Mice were treated for 3 days with the selective NOD1 agonist C12-iE-DAP (iE-DAP), and cardiac function and Ca(2+) 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 Ca(2+) current, [Ca(2+)]i transients and Ca(2+) load, and decreased expression of phospho-phospholamban, sarcoplasmic reticulum-ATPase, and Na(+)-Ca(2+) exchanger. Furthermore, iE-DAP prompted ''diastolic Ca(2+) leak'' in cardiomyocytes, resulting from increased Ca(2+) spark frequency and RyR2 over-phosphorylation. Importantly, these iE-DAP-induced changes in Ca(2+) 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-kappaB (BAY11-7082) prevented cardiac dysfunction and Ca(2+) 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-kappaB activation and uncover a new pro-inflammatory player in the regulation of cardiovascular function. |
