Oncotarget

Research Papers:

Inhibition of autophagy inhibits the conversion of cardiac fibroblasts to cardiac myofibroblasts

Shivika S. Gupta, Matthew R. Zeglinski, Sunil G. Rattan, Natalie M. Landry, Saeid Ghavami, Jeffrey T. Wigle, Thomas Klonisch, Andrew J. Halayko and Ian M.C. Dixon _

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Oncotarget. 2016; 7:78516-78531. https://doi.org/10.18632/oncotarget.12392

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Abstract

Shivika S. Gupta1, Matthew R. Zeglinski1, Sunil G. Rattan1, Natalie M. Landry1, Saeid Ghavami2,3, Jeffrey T. Wigle5, Thomas Klonisch2, Andrew J. Halayko3,4, Ian M.C. Dixon1

1Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

2Department of Human Anatomy and Cell Science, Basic Medical Sciences Building, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

3Children’s Hospital Research Institute of Manitoba, John Buhler Research Centre, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

4Department of Physiology and Pathophysiology, Internal Medicine and Pediatrics and Child Health, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

5Department of Biochemistry and Medical Genetics, Institute of Cardiovascular Sciences, Rady Faculty of Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

Correspondence to:

Ian M.C. Dixon, email: idixon@sbrc.ca

Keywords: cardiac fibroblast, myofibroblast, phenoconversion, autophagy, cardiac fibrosis

Received: August 04, 2016     Accepted: September 20, 2016     Published: October 01, 2016

ABSTRACT

The incidence of heart failure with concomitant cardiac fibrosis is very high in developed countries. Fibroblast activation in heart is causal to cardiac fibrosis as they convert to hypersynthetic cardiac myofibroblasts. There is no known treatment for cardiac fibrosis. Myofibroblasts contribute to the inappropriate remodeling of the myocardial interstitium, which leads to reduced cardiac function and ultimately heart failure. Elevated levels of autophagy have been linked to stress-induced ventricular remodeling and other cardiac diseases. Previously, we had shown that TGF-β1 treatment of human atrial fibroblasts both induced autophagy and enhanced the fibrogenic response supporting a linkage between the myofibroblast phenotype and autophagy. We now demonstrate that with in vitro culture of primary rat cardiac fibroblasts, inhibition of autophagy represses fibroblast to myofibroblast phenoconversion. Culturing unpassaged cardiac fibroblasts for 72 hours on plastic tissue culture plates is associated with elevated α-smooth muscle actin (α-SMA) expression. This activation parallels increased microtubule-associated protein 1A/1B-light chain 3 (LC-3β II) protein expression. Inhibition of autophagy with bafilomycin-A1 (Baf-A1) and chloroquine (CQ) in cardiac fibroblasts significantly reduces α-SMA and extracellular domain A fibronectin (ED-A FN) protein vs untreated controls. Myofibroblast cell migration and contractility were significantly reduced following inhibition of autophagy. These data support the possibility of a causal link between cardiac fibroblast-to-myofibroblast phenoconversion and autophagy.


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