NOD1 Activation Induces Cardiac Dysfunction and Modulates Cardiac Fibrosis and Cardiomyocyte Apoptosis

Abstract

The innate immune system is responsible for the initial response of an organism to potentially harmful stressors, pathogens or tissue injury, and accordingly plays an essential role in the pathogenesis of many inflammatory processes, including some cardiovascular diseases. Toll like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLRs) are pattern recognition receptors that play an important role in the induction of innate immune and inflammatory responses. There is a line of evidence supporting that activation of TLRs contributes to the development and progression of cardiovascular diseases but less is known regarding the role of NLRs. Here we demonstrate the presence of the NLR member NOD1 (nucleotide-binding oligomerization domain containing 1) in the murine heart. Activation of NOD1 with the specific agonist C12-iEDAP, but not with the inactive analogue iE-Lys, induces a time- and dose-dependent cardiac dysfunction that occurs concomitantly with cardiac fibrosis and apoptosis. The administration of iEDAP promotes the activation of the NF-κB and TGF-β pathways and induces apoptosis in whole hearts. At the cellular level, both native cardiomyocytes and cardiac fibroblasts expressed NOD1. The NLR activation in cardiomyocytes was associated with NF-κB activation and induction of apoptosis. NOD1 stimulation in fibroblasts was linked to NF-κB activation and to increased expression of pro-fibrotic mediators. The down-regulation of NOD1 by specific siRNAs blunted the effect of iEDAP on the pro-fibrotic TGF-β pathway and cell apoptosis. In conclusion, our report uncovers a new pro-inflammatory target that is expressed in the heart, NOD1. The specific activation of this NLR induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis, pathological processes involved in several cardiac diseases such as heart failure.

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…However in an aortic banding model of pressure overload, NOD2 deletion exacerbated adverse myocardial remodelling [63]. Although results from NOD1 knockout mice have not been reported for the heart, NOD1 activation induced cardiac dysfunction with increased cardiac fibrosis and cardiomyocyte apoptosis [26], suggesting a detrimental role for this receptor in this context. RAGE knockout has beneficial effects following myocardial ischaemia/reperfusion injury [64,65], in keeping with other studies focused on RAGE activity in cardiac remodelling [66].…”

“…Activation of these receptors is often coupled to inflammatory responses driven by NF B signalling [13,16], although proliferative, migratory and fibrotic outcomes have also been observed in response to different ligands [23][24][25][26].…”

“…However, there is evidence for functional expression of TLR2 [57,73], TLR3 [73], TLR4 [68,73,74] and TLR9 [73,75] in CF. Of the known members of the NLR family, CF express NOD1 and NOD2 [26,62], as well as the inflammasome-associated NLRP3 [73,76] RAGE is expressed in several cell types within the heart [64] and in cultured human and rodent CF [23,[77][78][79].…”

“…Both NOD1 and NOD2 are expressed by CF and appear to play important roles in regulating cardiac remodelling [26,62]. A NOD1-specific ligand (C12-iE-DAP) induced NF B and TGF pathway activation in CF, and promoted inflammatory signalling, apoptosis, fibrosis and cardiac dysfunction in mice [26].…”

“…A NOD1-specific ligand (C12-iE-DAP) induced NF B and TGF pathway activation in CF, and promoted inflammatory signalling, apoptosis, fibrosis and cardiac dysfunction in mice [26]. NOD2 expression was elevated in the infarcted area in a mouse MI model, and NOD2 knockout mice had improved cardiac function, less inflammation and less remodelling after MI compared with wild-type animals [62].…”