Abstract 68: Role of Substance P Signaling in the Pathogenesis of Murine Viral Myocarditis
Viral myocarditis is an important cause of heart failure in adolescents and young adults for which no specific treatment is currently available. Substance P (SP) is a neuropeptide and pain transmitter that activates RhoA, a small G-protein, shown to induce hypertrophy of neonatal rat ventricular myocytes. The current studies were performed to determine if SP signaling contributes to the pathogenesis of encephalomyocarditis virus (EMCV) infection, a well-established murine model of viral myocarditis. Aprepitant (1.2 mg/kg), a SP receptor antagonist, or fasudil (10mg/kg), a Rho A inhibitor, or saline control, was administered daily to mice orally by gavage 3 times for 3 days prior to intraperitoneal infection with 50 PFU of EMCV, and the mice monitored for 14 days. Pretreatment with aprepitant reduced mortality by 40% (25±7% vs. 65±7%), reduced heart-to-body weight ratio by 26% (0.0088±0.0001 vs. 0.0119±0.0001), reduced end systolic diameter (ESD) by 21% (3.0±0.2mm vs. 3.8±0.4mm), improved ejection fraction by 72% (57.2±4.7% vs. 33.2 ±9.3%), reduced chamber volume by 46% (34±5.0 μl vs. 62.7±30.8 μl), increased peak aortic flow velocity by 41% (87.0±24.7 vs. 61.7±20.1), and reduced cardiomyocyte diameter size by13% (11.0±0.1 μM vs. 12.7± 0.2 μM); p<.05 for all, Student’s t-test). Pretreatment with fasudil reduced heart-to-body weight ratio by 18% (0.0097±0.0001 vs. 0.0119±0.0001) and reduced cardiomyocyte diameter size by 12% (11.14±0.51 μM vs. 12.7± 0.2 μM; p<.05 for both), but did not significantly impact heart functional changes or mortality. These findings indicate that SP contributes to cardiac remodeling and dysfunction following ECMV infection and raises the possibility that inhibition of SP signaling may be of benefit in the treatment of patients with viral myocarditis.
- © 2012 by American Heart Association, Inc.