P5274
VCP979, a novel p38MAPK inhibitor, attenuates inflammatory response and improve cardiac function post-myocardial infarction

Extract

Background: Following myocardial infarction (MI), a localised inflammatory response occurs and progressive myocardium structural changes leading to left ventricular (LV) dysfunction. Evidence indicates that p38 mitogen-activated protein kinase (p38 MAPK) may be a common intracellular signalling pathway involved in cardiac remodelling and maladaptive processes post-MI.

Purpose: The aim of this study was to determine the anti-hypertrophy, anti-fibrosis and anti-inflammatory effects of a novel p38MAPK inhibitor, VCP979, in vitro and its in vivo efficacy in post-MI.

Methods: Cultured rat neonatal cardiac myocyte (NCM) hypertrophy stimulated with angiotensin II (AngII 100nM, 60hrs; IL-1β & TNFα, 10ng/ml, 48hrs) and fibroblast (NCF) collagen synthesis (stimulated by AngII, 100nM & TGFβ, 10ng/ml, 48hrs) were determined by [3H]-leucine and [3H]-proline incorporation, respectively. Lipopolysaccharides (LPS, 500ng/ml, 18hrs) stimulated THP-1 cell inflammatory cytokine (IL-6, IL-1β and TNFα) gene expression were determined by q-PCR. Cells were pre-treated with VCP979 (0.1 to 3μM) for 1 hour before stimulation and analysis performed as previous reported protocols. MI was introduced by left anterior descending coronary artery in C57BL/6 mouse (6∼8 weeks age, ∼20grams) followed by treatment with VCP979 (50mg/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, immunohistochemistry and gene expression assays.