scholarly journals Targeted inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis and Preserves Heart Function in Adverse Cardiac Remodeling

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Jie Zhang ◽  
Guangpu Fan ◽  
Hui Zhao ◽  
Zhiwei Wang ◽  
Fei Li ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Heart Function ◽  
Targeted Inhibition

scholarly journals Pharmacological Inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis in Mice Cardiac Fibroblast and Post-Myocardial-Infarction Models

2015 ◽  
Vol 37 (2) ◽  
pp. 515-526 ◽  
Author(s):  
Guang-Pu Fan ◽  
Wei Wang ◽  
Hui Zhao ◽  
Lin Cai ◽  
Pei-De Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Heart Function ◽  
Smooth Muscle Actin ◽  
Post Myocardial Infarction ◽  
Type I ◽  
Pharmacological Inhibition

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. Conclusion: This study provides novel evidence that FAK inhibition may become a promising pharmaceutical strategy to attenuate fibrosis post-MI.

scholarly journals Activation of pyk2/Related Focal Adhesion Tyrosine Kinase and Focal Adhesion Kinase in Cardiac Remodeling

2002 ◽  
Vol 277 (47) ◽  
pp. 45203-45210 ◽  
Author(s):  
Jaime Melendez ◽  
Sara Welch ◽  
Erik Schaefer ◽  
Christine S. Moravec ◽  
Shalom Avraham ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cardiac Remodeling

scholarly journals Focal adhesion kinase regulates early steps of myofibrillogenesis in cardiomyocytes

2018 ◽  
Author(s):  
Nilay Taneja ◽  
Abigail C. Neininger ◽  
Matthew R. Bersi ◽  
W. David Merryman ◽  
Dylan T. Burnette
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
De Novo ◽  
Heart Function ◽  
Focal Adhesions ◽  
Induced Pluripotent Stem Cell ◽  
Force Balance ◽  
Human Cardiomyocytes ◽  
Induced Pluripotent ◽  
The Stability

AbstractForces generated by myofibrils within cardiomyocytes must be balanced by adhesion to the substrate and to other cardiomyocytes for proper heart function. Loss of this force balance results in cardiomyopathies that ultimately cause heart failure. How this force balance is first established during the assembly of myofibrils is poorly understood. Using human induced pluripotent stem cell derived cardiomyocytes, we show coupling of focal adhesions to myofibrils during early steps of de novo myofibrillogenesis is essential for myofibril maturation. We also establish a key role for Focal adhesion kinase (FAK), a known regulator of adhesion dynamics in non-muscle cells, in regulating focal adhesion dynamics in cardiomyocytes. Specifically, FAK inhibition increased the stability of vinculin in focal adhesions, allowing greater substrate coupling of assembling myofibrils. Furthermore, this coupling is critical for regulating myofibril tension and viscosity. Taken together, our findings uncover a fundamental mechanism regulating the maturation of myofibrils in human cardiomyocytes.

Novel strategies to attenuate skin fibrosis: Targeted inhibition of focal adhesion kinase in dermal fibroblasts

2010 ◽  
Vol 211 (3) ◽  
pp. S127
Author(s):  
Michael Sorkin ◽  
Victor W. Wong ◽  
Kristine C. Rustad ◽  
Jason P. Glotzbach ◽  
Melanie R. Major ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Dermal Fibroblasts ◽  
Skin Fibrosis ◽  
Targeted Inhibition

Early signalling events of autophagy

2013 ◽  
Vol 55 ◽  
pp. 1-15 ◽  
Author(s):  
Laura E. Gallagher ◽  
Edmond Y.W. Chan
Keyword(s):  
Protein Kinase ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Mammalian Cells ◽  
Mammalian Target Of Rapamycin ◽  
Interacting Protein ◽  
The Core ◽  
Autophagy Gene ◽  
Autophagy Induction ◽  
Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

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