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

Fan, Guangpu; Wang, Wei; Zhao, Hui; Lin, Cai; Zhang, Peide; Yang, Zihe; Zhang, Jing; Wang, Xu

doi:10.1159/000430373

Cited by 45 publications

(34 citation statements)

References 25 publications

(43 reference statements)

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“…Accumulating evidence has demonstrated that excessive fibrosis would lead to ventricular dilation, infarct expansion, and heart failure [9-11]. Thus, effective interventions to inhibit cardiac fibrosis may have potential therapeutic effects on improving heart function and even reducing mortality risk [12-14]. …”

Section: Introductionmentioning

confidence: 99%

Mir-21 Promotes Cardiac Fibrosis After Myocardial Infarction Via Targeting Smad7

Yuan

Chen

et al. 2017

Cell Physiol Biochem

191

140

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Background/Aims: Cardiac fibrosis after myocardial infarction (MI) has been identified as an important factor in the deterioration of heart function. Previous studies have demonstrated that miR-21 plays an important role in various pathophysiological processes in the heart. However, the role of miR-21 in fibrosis regulation after MI remains unclear. Methods: To induce cardiac infarction, the left anterior descending coronary artery was permanently ligated of mice. First, we explored the expression of miR-21 in the infarcted zone in mice model of MI via RT-qPCR. Next, we examined the effects of TGF-β1 on miR-21 expression in cardiac fibroblasts (CFs). Then, CFs were infected with miR-21 mimics or miR-21 inhibitors to investigate the effects of miR-21 on the process of CFs activation in vitro. Further, bioinformatics analysis and luciferase reporter assay were performed to identify and validate the target gene of miR-21. At last, in-vivo study was done to confirm MiR-21 regulated myocardial fibrosis after MI in mice. Results: MiR-21 was up-regulated in the infarcted zone after MI in vivo. TGF-β1 treatment increased miR-21 expression in CFs. Overexpression of miR-21 promoted the effects of TGF-β1-induced activation of CFs, evidenced by increased expression of Col-1, α-SMA and F-actin, whereas inhibition of miR-21 attenuated the process of fibrosis. Bioinformatics, Western blot analysis and luciferase reporter assay demonstrated that Smad7 is a direct target of miR-21. In addition, in-vivo study revealed that MiR-21 regulated myocardial fibrosis after MI in mice. Conclusion: These findings suggested that miR-21 has a critical role in CF activation and cardiac fibrosis after MI through via TGF-β/Smad7 signaling pathway. Thus, miR-21 promises to be a potential therapy in treatment of cardiac fibrosis after MI.

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Section: Introductionmentioning

confidence: 99%

Mir-21 Promotes Cardiac Fibrosis After Myocardial Infarction Via Targeting Smad7

Yuan

Chen

et al. 2017

Cell Physiol Biochem

191

140

View full text Add to dashboard Cite

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“…We also showed that in contrast to LRP1 inhibition, PP2 expression did not alter vascular cell pro‐inflammatory phenotypes. PP2‐mediated Pyk2 phosphorylation inhibition has been shown to efficiently reverse fibrosis development in a load‐induced cardiac hypertrophy mouse model and to attenuate fibrosis after MI . Here, we showed for the first time the temporal and spatial evolution of pPyk2 levels after MI.…”

Section: Discussionmentioning

confidence: 63%

Relationship among LRP1 expression, Pyk2 phosphorylation and MMP‐9 activation in left ventricular remodelling after myocardial infarction

Revuelta‐López

Soler‐Botija

Nasarre

et al. 2017

J Cellular Molecular Medi

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Left ventricular (LV) remodelling after myocardial infarction (MI) is a crucial determinant of the clinical course of heart failure. Matrix metalloproteinase (MMP) activation is strongly associated with LV remodelling after MI. Elucidation of plasma membrane receptors related to the activation of specific MMPs is fundamental for treating adverse cardiac remodelling after MI. The aim of current investigation was to explore the potential association between the low‐density lipoprotein receptor‐related protein 1 (LRP1) and MMP‐9 and MMP‐2 spatiotemporal expression after MI. Real‐time PCR and Western blot analyses showed that LRP1 mRNA and protein expression levels, respectively, were significantly increased in peri‐infarct and infarct zones at 10 and 21 days after MI. Confocal microscopy demonstrated high colocalization between LRP1 and the fibroblast marker vimentin, indicating that LRP1 is mostly expressed by cardiac fibroblasts in peri‐infarct and infarct areas. LRP1 also colocalized with proline‐rich tyrosine kinase 2 (pPyk2) and MMP‐9 in cardiac fibroblasts in ischaemic areas at 10 and 21 days after MI. Cell culture experiments revealed that hypoxia increases LRP1, pPyk2 protein levels and MMP‐9 activity in fibroblasts, without significant changes in MMP‐2 activity. MMP‐9 activation by hypoxia requires LRP1 and Pyk2 phosphorylation in fibroblasts. Collectively, our in vivo and in vitro data support a major role of cardiac fibroblast LRP1 levels on MMP‐9 up‐regulation associated with ventricular remodelling after MI.

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“…The MI model was characterized as previously described (Fan et al, 2015). Mice were anesthetized by intraperitoneal administration of tribromoethanol (400 mg/kg) and ventilated with a rodent respirator, then the left anterior descending coronary artery was permanently occluded using a 7-0 polypropylene suture, and the occlusion was confirmed by blanching of the anterior wall of the left ventricle.…”

Section: Methodsmentioning

confidence: 99%

Protective Role for LPA3 in Cardiac Hypertrophy Induced by Myocardial Infarction but Not by Isoproterenol

et al. 2017

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Background: We previously reported that lysophosphatidic acid (LPA) promoted cardiomyocyte hypertrophy in vitro via one of its G protein-coupled receptor subtypes, LPA3. In this study, we examined the role of LPA3 in cardiac hypertrophy induced by isoproterenol (ISO) and myocardial infarction.Methods: In vitro, neonatal rat cardiomyocytes (NRCMs) were subjected to LPA3 knocked-down, or pretreated with a β-adrenergic receptor (β-AR) antagonist (propranolol) before LPA/ISO treatment. Cardiomyocyte size and hypertrophic gene (ANP, BNP) mRNA levels were determined. In vivo, LPA3-/- and wild-type mice were implanted subcutaneously with an osmotic mini-pump containing ISO or vehicle for 2 weeks; echocardiography was performed to determine the heart weight/body weight ratio, cardiomyocyte cross-sectional area, and level of ANP mRNA expression. LPA3-/- and wild-type mice were subjected to permanent coronary artery ligation or sham surgery for 4 weeks; cardiac function, including the degree of hypertrophy and infarction size, was determined.Results: In vitro, we found that knocked-down LPA3 in NRCMs did not attenuate ISO-induced hypertrophy, and propranolol was unable to abolish LPA-induced hypertrophy. In vivo, chronic ISO infusion caused cardiac hypertrophy in wild-type mice, while hypertrophic responses to ISO infusion were not attenuated in LPA3-/- mice. However, in a myocardial infarction (MI) model, LPA3-/- mice exhibited reduced cardiac hypertrophy compared to wild-type mice at 4 weeks post-MI, which was associated with reduced cardiac function and increased infarct size.Conclusions: Our data show that LPA3 appears to play a protective role in myocardial hypertrophy post-MI, but does not appear to be involved in the hypertrophy that occurs in response to β-AR stimulation in vivo and in vitro. These results implicate LPA-LPA3 lipid signaling in cardiac hypertrophy occurring after pathological insults like MI, which presents a new variable in β-AR-independent hypertrophy. Thus, modulation of LPA3 signaling might represent a new strategy for preventing the stressed myocardium from ischemia injury.

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

Cited by 45 publications

References 25 publications

Mir-21 Promotes Cardiac Fibrosis After Myocardial Infarction Via Targeting Smad7

Mir-21 Promotes Cardiac Fibrosis After Myocardial Infarction Via Targeting Smad7

Relationship among LRP1 expression, Pyk2 phosphorylation and MMP‐9 activation in left ventricular remodelling after myocardial infarction

Protective Role for LPA3 in Cardiac Hypertrophy Induced by Myocardial Infarction but Not by Isoproterenol

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