Format

Send to

Choose Destination
JCI Insight. 2019 Jan 10;4(1). pii: 92098. doi: 10.1172/jci.insight.92098. [Epub ahead of print]

Exercise promotes a cardioprotective gene program in resident cardiac fibroblasts.

Author information

1
Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
2
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA.
3
Department of Medicine.
4
Department of Allergy, Immunology, and Rheumatology Research, and.
5
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.

Abstract

Exercise and heart disease both induce cardiac remodeling, but only disease causes fibrosis and compromises heart function. The cardioprotective benefits of exercise have been attributed to changes in cardiomyocyte physiology, but the impact of exercise on cardiac fibroblasts (CFs) is unknown. Here, RNA-sequencing reveals rapid divergence of CF transcriptional programs during exercise and disease. Among the differentially expressed programs, NRF2-dependent antioxidant genes - including metallothioneins (Mt1 and Mt2) - are induced in CFs during exercise and suppressed by TGF-β/p38 signaling in disease. In vivo, mice lacking Mt1/2 exhibit signs of cardiac dysfunction in exercise, including cardiac fibrosis, vascular rarefaction, and functional decline. Mechanistically, exogenous MTs derived from fibroblasts are taken up by cultured cardiomyocytes, reducing oxidative damage-dependent cell death. Importantly, suppression of MT expression is conserved in human heart failure. Taken together, this study defines the acute transcriptional response of CFs to exercise and disease and reveals a cardioprotective mechanism that is lost in disease.

KEYWORDS:

Cardiology; Cardiovascular disease; Cell Biology; Expression profiling; Fibrosis

PMID:
30626739
DOI:
10.1172/jci.insight.92098
Free full text

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation
Loading ...
Support Center