Role of autophagy in cardiac fibroblast activation in cardiac fibrosis
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Date
2016-10-01
Authors
Gupta, Shivika
Journal Title
Journal ISSN
Volume Title
Publisher
Impact Journals - Oncotarget
Abstract
Following myocardial infarction (MI), initial cardiac remodeling or wound repair/healing is beneficial and required for continued function. During the wound healing phase, cardiac fibroblasts activate to become contractile and hypersynthetic myofibroblasts and contribute to cardiac fibrosis. Chronic cardiac remodeling leads to the development of overt cardiac hypertrophy and excessive extracellular matrix (ECM) deposition with attendant loss of myocardial performance. There is no treatment that prevents or reverses fibrosis in the post-MI heart. Induction of autophagy is linked to stress-induced ventricular remodeling in various cardiac diseases and has not been well studied in fibroblast activation. As the plating of primary cardiac fibroblasts on incompressible plastic substrate leads to activation of these cells, we used this model system in primary rat cardiac fibroblasts to examine the relationship between autophagy and fibroblast activation. 72 hours after plating of fibroblasts, we observed the concomitant increase in expression of myofibroblast markers and induction of autophagy, assessed via western blotting, immunofluorescence, and transmission electron microscopy. Treatment with inhibitors of autophagy (BafilomycinA1 (Baf-A1), 3-methyladenine (3MA), and chloroquine (CQ) decreased myofibroblast marker expression and reduced myofibroblast contractility (assessed by collagen gel contraction assay). CQ treatment suppressed fibroblast activation in unpassaged P0 cardiac fibroblasts. We used the coronary artery ligation rat model of MI to further explore the effects of CQ administration in development of cardiac fibrosis. At 4 and 8 weeks post-MI, there was no significant change in ventricular function (assessed via echocardiography), however in isolated cardiac tissue treated with CQ, we observed a decrease in myofibroblast marker expression. We also show increased autophagy in the MI group animal. We also studied tissue fibrosis by comparing the collagen accumulation between CQ treated and nontreated animals. Although CQ treatment was associated with a decrease in -SMA expression in the 4 week post-MI group, there was no difference seen on collagen level among the same study groups. These data support a causal link between autophagy and activation of cardiac fibroblast. This study provides a new avenue for therapeutic options to suppress the activation of cardiac fibroblasts and thereby reduce cardiac fibrosis.
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Keywords
Autophagy, Cardiac fibroblast, Cardiac fibrosis
Citation
APA