Atypical MAPK ERK3 is required for the development of interstitial fibrosis during pressure overload‐induced hypertrophy

The interstitial fibrosis associated with cardiac hypertrophy results in impaired cardiac function. p38 MAPK, which has been implicated in cardiac fibrosis, is known to regulate MK5. MK5 is also under the control of atypical MAPKs, ERK3 and ERK4, although physiological role of ERK3/4 remains unknown. We recently reported reduced fibrosis in MK5+/− mice following 2‐ and 3‐weeks transverse aortic constriction (TAC) (FASEB J, 2010, 24:521.1). Hence, we hypothesized that ERK3‐MK5 signaling is involved in reactive fibrosis. Therefore, we examined the effect of TAC‐induced pressure overload in ERK3+/− and ERK3+/+ mice. Three weeks after TAC, LVP, HW/BW ratio, BNP, and β‐MHC mRNA levels were significantly and similarly increased in both ERK3+/− and ERK3+/+ hearts (p<0.001, n=7–8). Furthermore, less collagen deposition, assessed by Masson trichrome staining, was observed in ERK3+/− hearts (n=7–8). Additionally, TAC‐induced increases in collagen α1 type1 mRNA levels were significantly lower in ERK3+/− mice (p<0.001, n=7–8). Immunoprecipitation of MK5 resulted in the co‐immunoprecipitation of ERK3, but not ERK4 or p38α, in lysates from both sham‐operated and 3 wk TAC hearts (n=3). Hence, in the heart ERK3, not ERK4 or p38α, forms a stable complex with MK5. These results demonstrate that ERK3‐MK5 signaling plays an important role in the increase in interstitial fibrosis induced by chronic pressure overload.