Differential regulation of mitogen-activated protein kinase signaling pathways in human with different types of mitral valvular disease

Background: Mitogen-activated protein kinases (MAPKs) are considered to play a prominent role in cardiac development, function, and pathogenesis. The different types of mitral valvular disease (MVD), including mitral regurgitation (MR) and mitral stenosis (MS), have different underlying pathophysiologic changes, but the precise intracellular signal transduction mechanisms are not clear. Thus, we investigated the differential regulation of MAPK signaling pathways in humans with different types of MVD. Methods: Left atrial appendage tissue samples from 32 patients with MVD who were undergoing mitral valve replacement surgery were studied. Serum angiotensin II concentrations were measured using enzyme-linked immunosorbent assay. The expression of MAPK pathway-related genes and proteins was assessed using quantitative polymerase chain reaction, Western blot, and immunohistochemistry. Results: Echocardiography showed that patients with MS had a greater left atrial pressure overload than those with MR. The relative amounts of angiotensin II, extracellular signal-regulated kinase 1, p38 alpha, c-Jun N-terminal kinase 2, c-Fos, activating transcription factor 2, and c-Jun mRNA were significantly upregulated in those with MS compared with those with MR (P < 0.05). The serum angiotensin II concentrations were significantly increased in those with MS compared with those with MR(P = 0.017). Substantial changes in the phosphorylated forms of the MAPK proteins were detected. Phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated p38 were significantly increased in those with MS compared with those with MR (P < 0.001), and phosphorylated c-Jun N-terminal kinase in the MR group was significantly greater than that in the MS group (P < 0.001). Histologically, more serious myocardial cells losses, myolysis, and interstitial fibrosis were detected in the MS group. Conclusions: The different types of MVD have different hemodynamic characteristics, and different MAPK pathways were activated in the MR and MS groups, which could lead to diverse left atrial histologic changes. (C) 2013 Elsevier Inc. All rights reserved.