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Myocardial remodeling after myocardial infarction (MI) induces complex architectural changes involving the infarcted and non-infarcted myocardium. Although fibrosis and remodeling have been studied for centruies, the pathophysiological mechanisms underlying fibrosis still need exploration. Thus, there is an urgent need to develop innovative therapeutic strategies for the treatment of thislethal disease.
We previously reported that FAK is involved in atrial fibrosis, and FAK inhibitior suppresses α-SMA expressions in TGFβ1-induced fibroblasts, In the present study, we used primary cardiac fibroblasts (CFs) and established an MI animal model to test our hypothesis that FAK participates in the processes of hypoxia induced- and post-MI cardiac fibrosis in vitro and in vivo, respectively.
CFs were isolated from hearts of two- to four-day-old neonatal ICR mice and cultured in Dulbecco's Modified Eagle's Medium. After preparation, the CFs were randomly divided into thefollowing experimental groups: Group A:normal, Group B: normal+PF-573,228,Group C: hypoxia.Group D: hypoxia +PF-573,228.
MI was induced by permanent left anterior descending (LAD) coronary artery ligation (CAL). mice underwent sham operation where the ligature around the LAD was not tied. The mouse were randomly divided into the following experimental groups: Group A: sham, Group B: sham+PF-573,228, Group C:MI.Group D: MI +PF-573,228.
Type I collagen, FAK protein, phospho-FAK, mTOR, ERK1/2, AKT, PI3K levels were also analyzed by western blot and immunofluorescence staining, respectively. Heart tissues were examine by Masson's trichrome and Sirius red staining, respectively. Echocardiography was carried out at 1, 2, 3 month.
FAK inhibition with PF-573,228 significantly decreased CFs differentiation and collagen synthesis under hypoxia treatment. pharmacologic FAK inhibition with PF-573,228 could suppresse the activation of FAK in myofibroblasts, and attenuate cardiac fibrosis post-MI, paralleling with down-regulation of its relevant signaling pathways, including mTOR, PI3K/AKT and ERK1/2. Diastolic left ventricular anterior wall (LVAW), left ventricular internal dimension (LVID) and left ventricular volume were significantly different between the MI and control groups.
In vivo, PF-573,228 treatment resulted in fibrosis attenuation and improve heart function of MI mice. PF-573,228 may affect phospho-mTOR, phospho-ERK1/2, phospho-AKT and PI3K to exert its benefits. FAK can be activated either under hypoxia in CFs or MI in a mouse model to promote fibrosis. However, pharmacological inhibition of FAK can attenuate fibrosis response.
FAK involved in cardiac fibrosis post-MI,and this process involves a number of signaling pathways. pharmacological inhibit FAK with PF-573,228 could be attenuated cardiac fibrosis. Both PI3K/AKT and ERK1/2 signaling pathways are involved in CFs differentiation, This study provides novel evidence that FAK inhibition may become a promising pharmaceutical strategy to attenuate fibrosis post-MI.