Abstract 10848: Nod1/RIP2 Signaling Regulates Cardiac Hypertrophic Response After Pressure Overload State
Background: Since the discovery of Toll-like receptors (TLRs), evidence that has been progressively gathered implicates an important role of the innate immune system in the pathogenesis of heart failure. Recent studies have shown the existence of cytosolic pattern-recognition receptor (PRR) families including nucleotide-binding oligomerization domain (Nod)-like receptor (NLR) family. Both Nod1 and Nod2 are members of the NLR family and numerous studies have appeared documenting the role of Nod1 and Nod2 as key PRRs in innate immune responses. Although Nod1 is highly expressed in the heart and Nod2 is mainly expressed in immune cells and epithelial cells, the functional role of Nod1 and Nod2 in the heart is unclear.
Methods and Results: C57/BL6 wild-type (WT), Nod1-knockout (Nod1-/-), Nod2-knockout (Nod2-/-), and receptor interactive protein 2-knockout (RIP2-/-) mice underwent transverse aortic constriction (TAC) or sham operation. RIP2 is recognized as a critical adapter molecule for Nod1 and Nod2, and locates just downstream of these receptors. Nod1 and RIP2 proteins were upregulated in the heart after TAC. However Nod2 wasn’t. Nod1-/- and RIP2-/- mice had better survival rate and cardiac function, smaller heart and myocytes, and lower heart weight and lung weight after TAC than WT mice. There were no significant differences between WT mice and Nod2-/- mice in these parameters. In vitro study using neonatal mice cardiomyocytes showed reduced hypertrophic responses in Nod1-/- and RIP2-/- mice after phenylephrine (PE) treatment compared with WT mice. Inflammatory cell infiltration, cytokine expressions, activities of MMPs, fibrosis, ANP and BNP expressions, apoptosis, and autophagy were reduced in Nod1-/- mice after TAC compared with WT mice. Nf-kb signaling pathway, Caspase-1, and MAPK-GATA4/p300 signaling pathway were suppressed in Nod1-/- mice. Immunoprecipitation study and immunostaining showed that in addition to RIP2, TRAF6 and Caspase-1 were binding partners of Nod1.
Conclusion: Findings from the present study have suggested that Nod1/RIP2 signaling pathway contributed to adverse left ventricular remodeling during pressure overload through regulation of inflammatory responses and apoptosis.
- © 2013 by American Heart Association, Inc.