Pharmacological Inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis in Mice Cardiac Fibroblast and Post-Myocardial-Infarction Models.
BACKGROUND
To investigate the role of focal adhesion kinase (FAK)-mediated signaling in hypoxia-induced cardiac fibroblasts (CFs) differentiation and cardiac fibrosis post-myocardial infarction (MI) on a mice model.


METHODS
CFs of neonatal C57BL/6 mice were treated under normoxic, hypoxic, or hypoxic+PP2 (known as a Src kinase family inhibitor) conditions. Gene expressions of FAK, alpha-smooth muscle actin (α-SMA) and collagen type I alpha 1 (Col1α1), or α-SMA and vimentin levels were performed by RT-PCR and immunofluorescence staining, respectively. Thirty mice were surgically treated into Sham (n=7) and MI (n=23) groups; and FAK inhibitor PF-562271 was given to six survivor MI mice (as PF group, from 15 survivors). Heart function and collagenous tissues were examined by echocardiography, as well as by Masson‘s trichrome and Sirius red staining, respectively. Type I collagen, FAK protein, mTOR, ERK1/2, AKT, P70S6K and phospho-FAK levels were also analyzed.


RESULTS
FAK inhibition with PP2 significantly decreased CFs differentiation and collagen synthesis under hypoxia treatment. In vivo, PF-562271 treatment resulted in fibrosis attenuation; however, deteriorated heart function of MI mice could not be significantly improved. PF-562271 may affect phospho-mTOR (p<0.05), phospho-ERK1/2 (p<0.01), phospho-AKT (p<0.001) and phospho-P70S6K (p<0.05) 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.


CONCLUSIONS
This study provides novel evidence that FAK inhibition may become a promising pharmaceutical strategy to attenuate fibrosis post-MI.
Guang-Pu
GP
Fan
Wei
W
Wang
Hui
H
Zhao
Lin
L
Cai
Pei-De
PD
Zhang
Zi-He
ZH
Yang
Jing
J
Zhang
Xu
X
Wang
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology
C412373:AG 1879; D007211:Indoles; C527797:N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; D011743:Pyrimidines; D013449:Sulfonamides; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse