Abstract 418: Substance P and Mast Cell Interaction Exacerbates Pressure Overload-Induced Cardiac Remodeling

Abstract

This study was designed to test the hypothesis that cardiac sensory nerves and mast cells play a critical adverse role in transverse aortic constriction (TAC) pressure overload-induced heart failure. Moreover, the mechanism is mediated by the activation of protease activated receptor 2 (PAR-2) receptors primarily located on cardiac sensory nerves and neurokinin 1 receptors (NK-1, substance P) located on mast cells and fibroblasts. Groups (n=6/group) of male PAR-2 receptor KO, NK-1 KO, and wild type (WT) C57BL6 mice (26-28 g) were subjected to either sham or TAC surgery on day 1. Echocardiographic, biometric, and immunohistological analyses were performed on all groups of mice on day 14. At this time point, none of the structural echocardiographic parameters were significantly different between the TAC WT and the TAC NK-1 KO and TAC PAR-2 KO mice, except for the systolic left ventricular internal diameter ( TAC WT, 3.0±0.2, TAC NK-1 KO, 1.5±0.2, and TAC PAR-2 KO, 1.8±0.3 mm (sham WT, 2.2±0.1)). In contrast, the fractional shortening (FS) was significantly greater in the TAC NK-1 KO mice (50±4%) and the TAC PAR 2 KO mice (46±6%) compared with the TAC WT mice (24±3%) (sham WT mice 40±2%). The ejection fraction (EF) was also significantly greater in the TAC NK-1 KO mice (82±4%) and PAR-2 KO mice (76±5%) compared to the TAC WT mice (48±4%) (sham WT mice 71±3%). In addition, the ratios of heart weight to body weight and lung weight to body weight were less in the TAC NK-1 KO and TAC PAR-2 KO mice compared to the TAC WT mice and the interstitial collagen fraction was significantly less in the TAC NK-1 KO mice (0.6±0.2%) and TAC PAR-2 KO mice (1.1±0.1%) compared to the TAC WT mice (1.6 ±0.4%). Therefore, these data indicate that cardiac sensory nerves (via PAR-2 receptors) and mast cells (via NK-1 receptors) play a critical adverse role in pressure overload-induced heart failure suggesting that antagonists of either or both receptors may be novel therapeutic agents for the treatment of pressure-induced heart failure.