p38 Regulates Programmed Myofibroblast Differentiation and Fibrosis

Fibrosis is the excess collagen deposition that occurs with nearly every form of heart disease. A myriad of different stimuli including mechanical strain, cytokines and neuroendocrine effectors like TGFβ and Angiotensin II induce fibrotic matrix deposition. Current paradigms suggest that the differentiation of resident fibroblasts into myofibroblasts underlies the heart’s fibrotic response through yet unknown molecular mechanisms. Recently the p38 mitogen activated protein kinase (MAPK) signaling axis was implicated as a nodal pathway regulating myofibroblast differentiation in vitro , but never examined in vivo . To tactically address the role of p38 in the heart’s fibrotic response tamoxifen-inducible Cre recombinase knock-in mice (Tcf21 MCM ) were used to excise p38α from cardiac fibroblasts of conditional p38α knockout mice (p38 F/F ) subjected to ischemic injury. Deletion of p38 in fibroblasts reduced scar area by more than 50%, which we ascribe to the significantly reduced number of myofibroblasts in these hearts. Moreover, p38 F/F - Tcf21 MCM mice had markedly improved diastolic function relative to control littermates with intact p38 activity. Conversely, mice with fibroblast-specific expression of a constitutively active MAPK kinase 6 transgene (MKK6 Tg), which directly initiates p38α activity, developed interstitial and perivascular fibrosis at baseline. These mice had severe diastolic dysfunction in comparison to non-transgenic littermates with myofibroblasts present throughout heart. To investigate whether p38 MAPK regulates the fibrotic response in other tissues, p38α was deleted from activated dermal fibroblasts in mice using a tamoxifen-inducible periostin Cre recombinase (Postn MCM ) that were subjected to subcutaneous circular wounds. Mice lacking p38 signaling in activated fibroblasts had significantly delayed wound closure relative to p38 replete littermates, whereas mice expressing the activated MKK6 transgene in activated fibroblasts had accelerated wound closure and scarring suggesting that p38α activity in fibroblasts is universally vital to the fibrotic phase of wound healing. Collectively, these data suggest that p38 inhibition is a viable candidate for anti-fibrotic therapies.