ERK3‐MK5 regulates interstitial fibrosis during pressure‐overload hypertrophy

Abstract

Cardiac hypertrophy occurs when the myocyte is continuously exposed to increased external stimuli such as stretch, hemodynamic overload and/or an increase in neurohormonal factors. MK5 was originally identified as p38 regulated and activated kinase and the physiological role of MK5 remains unknown. Therefore, we studied the effect of transverse aortic constriction (TAC)‐induced pressure overload hypertrophy in mice heterozygous for a functional knockout of MK5 (MK5+/−) and their wild‐type (MK5+/+) littermates. Following 2‐wk of TAC, heart weight/body weight ratios were significantly (p<0.01, n=6–9) and similarly increased in both MK5+/− and MK5+/+ hearts. Transthoracic echocardiography revealed TAC reduced diastolic function in MK5+/+, but not in MK5+/− hearts. Less collagen deposition, assessed by Masson trichrome staining, was observed in MK5+/− hearts following both 2‐ and 3‐wks of TAC. Furthermore, TAC‐induced increases in collagen alpha1 type1 mRNA levels was significantly lower at both 2 (p<0.001 vs MK5+/+, n=6–9) and 3 (p<0.01 vs MK5+/+, n=8) wks of TAC. Immunoprecipitation of MK5 resulted in co‐immunoprecipitation of ERK3 but not ERK4 or p38α in control, sham‐operated and TAC hearts. These data suggest that MK5 associates with and is regulated by ERK3 but not ERK4 or p38α in heart. Furthermore, ERK3‐MK5 signaling may play a key role in reactive fibrosis during pressure overload hypertrophy.