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

Abstract

Cardiac fibrosis in post-myocardial infarction (MI), seen in both infarcted and non-infarcted myocardium, is beneficial to the recovery of heart function. But progressively pathological fibrosis impairs ventricular function and leads to poor prognosis. FAK has recently received attention as a potential mediator of fibrosis, our previous study reported that pharmacological inhibition of FAK can attenuate cardiac fibrosis in post MI models. However, the long-term effects on cardiac function and adverse cardiac remodelling were not clearly investigated. In this study, we tried to determine the preliminary mechanisms in regulating CF transformation to myofibroblasts and ECM synthesis relevant to the development of adverse cardiac remolding in vivo and in vitro. Our study provides even more evidence that FAK is directly related to the activation of CF in hypoxia condition in a dose-dependent and time-dependent manner. Pharmacological inhibition of FAK significantly reduces myofibroblast differentiation; our in vivo data demonstrated that a FAK inhibitor significantly decreases fibrotic score, and preserves partial left ventricular function. Both PI3K/AKT signalling and ERK1/2 are necessary for hypoxia-induced CF differentiation and ECM synthesis; this process also involves lysyl oxidase (LOX). These findings suggest that pharmacological inhibition of FAK may become an effective therapeutic strategy against adverse fibrosis.

Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis

“…Here, we show that targeting FAK signaling with PF-562,271 rapidly suppresses the expression of BCL-X L and induces apoptosis of stiffnessprimed myofibroblasts, providing new insight into the mechanistic basis behind the potent antifibrotic effects of FAK inhibitors (12,14,48,49,(53)(54)(55)(56)(57).…”

PTEN improve renal fibrosis in vitro and in vivo through inhibiting FAK/AKT signaling pathway

“…As a cytoplasmic protein tyrosine kinase, FAK serves as a key factor in the process of embryo development and in the pathogenesis of human diseases, such as cancer, cardiovascular diseases, and fibrosis . FAK has been found to be expressed in the majority of tissues and its sequence is high conservation among species.…”

“…In HK-2 cells, PTEN expression was significantly suppressed by 24 As a cytoplasmic protein tyrosine kinase, FAK serves as a key factor in the process of embryo development and in the pathogenesis of human diseases, such as cancer, cardiovascular diseases, and fibrosis. [25][26][27][28] FAK has been found to be expressed in the majority of tissues and its sequence is high conservation among species. Reportedly, FAK has been regarded as a key factor which enhances downstream cell survival and growth of ECM-induced integrin signaling, while integrin mutants with endocytic defect inhibit integrin-mediated pFAK-Y397, pAkt-S473, and pErk1/2 signaling.…”

The interplay between extracellular matrix remodelling and kinase signalling in cancer progression and metastasis

“…Finally, the ability for downstream signalling pathways in tumour cells to respond to changes in the ECM can also be targeted through inhibitors of FAK/SRC pathways 49,50 which can uncouple the effects of ECM remodelling on cell proliferation and tumour progression. A similar role has been shown in a non-cancer setting for cardiac fibroblasts following myocardial infarction.…”

“…A similar role has been shown in a non-cancer setting for cardiac fibroblasts following myocardial infarction. 50 Collectively, this approach to targeting ECM remodelling and its effects on signalling programs within tumour and stromal cells has the potential to reduce tumour burden both at the primary tumour and also at secondary sites.…”