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NOD1, a new player in cardiac function and calcium handling

AuthorsDelgado, Carmen ; Ruiz-Hurtado, Gema; Gómez-Hurtado, Nieves; González-Ramos, Silvia; Benito, Gemma; Prieto, Patricia ; Zaragoza, Carlos; Delicado, Esmerilda G.; Pérez-Sen, Raquel; Miras-Portugal, María Teresa; Boscá, Lisardo ; Fernández-Velasco, María
Issue Date2015
PublisherOxford University Press
CitationCardiovascular Research 106(3): 375-386 (2015)
Abstract[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-κB (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-κB activation and uncover a new pro-inflammatory player in the regulation of cardiovascular function.
Descriptionet al.
Identifiersdoi: 10.1093/cvr/cvv118
issn: 0008-6363
e-issn: 1755-3245
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