NOD2 Deficiency Protects against Cardiac Remodeling after Myocardial Infarction in Mice

Abstract

Background/Aims: Although the pathogenesis of myocardial infarction (MI) is multifactorial, activation of innate immune system to induce inflammation has emerged as a key pathophysiological process in MI. NOD2, one member of the NOD-like receptor (NLR) family, plays an important role in the innate immune response. This study was to examine the role of NOD2 during MI. Methods: MI was induced by permanent ligation of the left coronary artery in wild type and NOD2^-/- mice and cardiac fibroblasts were isolated. Results: NOD2 expression was significantly increased in myocardium in post-MI mice. NOD2 deficiency improved cardiac dysfunction and remodeling after MI as evidenced by echocardiographic analysis, reduced the levels of cytokines, inflammatory cell infiltration and matrix metalloproteinase-9 (MMP-9) activity. In vitro, we further found that NOD2 activation induced the activation of MAPK signaling pathways, production of proinflammatory mediators and MMP-9 activity in cardiac fibroblasts. Conclusions: Our studies demonstrate that NOD2 is a critical component of a signal transduction pathway that links cardiac injury by exacerbation of inflammation and MMP-9 activity. Pharmacological targeting of NOD2-mediated signaling pathways may provide a novel approach to treatment of cardiovascular diseases.

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

“…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]. An important role for fibroblasts was suggested in this model as NOD2 activation induced MAPK signalling, proinflammatory cytokine production and MMP-9 activation in CF; outcomes that were inhibited by NOD2 RNA interference [62]. Most known NOD1/2 ligands are pathogenassociated molecular patterns, rather than DAMPs, so the precise DAMP ligands that activate NOD1 and NOD2 receptors in the heart requires further analysis.…”

“…In a permanent left anterior descending coronary artery ligation model of MI, NOD2 knockout mice had improved cardiac function and reduced inflammation [62]. However in an aortic banding model of pressure overload, NOD2 deletion exacerbated adverse myocardial remodelling [63].…”

“…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]. An important role for fibroblasts was suggested in this model as NOD2 activation induced MAPK signalling, proinflammatory cytokine production and MMP-9 activation in CF; outcomes that were inhibited by NOD2 RNA interference [62].…”