P5274VCP979, a novel p38MAPK inhibitor, attenuates inflammatory response and improve cardiac function post-myocardial infarction

Background: p38 mitogen-activated protein kinase (p38 MAPK) is a common intra-cellular signalling pathway involved in cardiac remodelling and maladaptive processes post-myocardial infarction (MI). The aim of this study was to determine the beneficial effects in vitro and in vivo efficacy of a novel p38 MAPK inhibitor, VCP979, post-MI. Methods: Cultured rat neonatal cardiac myocyte (NCM) hypertrophy stimulated with angiotensin II (AngII 100 nM, 60 hrs; IL-1β and TNFα, 10 ng/ml, 48 hrs) and fibroblast (NCF) collagen synthesis (stimulated by AngII, 100 nM and TGFβ, 10 ng/ml, 48 hrs) were determined by [3H]-leucine and [3H]-proline incorporation, respectively. Lipopolysaccharides (LPS, 500 ng/ml, 18 hrs) stimulated THP-1 cell inflammatory cytokine (IL-6, IL-1β and TNFα) gene expression were determined by q-PCR. MI was introduced by LAD ligation in C57BL/6 mouse (6∼8 weeks age, ∼20grams) followed by treatment with VCP979 (50 mg/kg/day, IP or PO) started 1 week after surgery for 4 weeks using ramipril as positive control. Echocardiography performed at baseline and endpoint and tissues harvested for protein and gene expression assays. Results: VCP979 dose-dependently inhibited AngII, IL-1β and TNFα stimulated NCM hypertrophy, AngII and TGFβ stimulated NCF collagen synthesis, and LPS stimulated IL-6, IL-1β and TNFα gene expression. VCP979 significantly improved cardiac function and reduced hypertrophy (Fig. 1). Conclusion: This study has demonstrated that the novel p38MAPK inhibitor, VCP979, can reduce cardiac hypertrophy and fibrosis in vitro and in vivo. Together with its anti-inflammatory effect, VCP979 is likely to be a novel therapeutic agent for the management of heart failure post-MI.