Abstract
Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, a minor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.
Keywords:
Col5a1; cilengitide; collagen V; fibrosis; heart scar; integrins; scar mechanics.
Copyright © 2020 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Cicatrix / genetics
-
Cicatrix / metabolism*
-
Cicatrix / physiopathology
-
Collagen Type I / genetics
-
Collagen Type I / metabolism
-
Collagen Type I, alpha 1 Chain
-
Collagen Type III / genetics
-
Collagen Type III / metabolism
-
Collagen Type V / deficiency*
-
Collagen Type V / genetics
-
Collagen Type V / metabolism*
-
Extracellular Matrix / genetics
-
Extracellular Matrix / metabolism
-
Female
-
Fibrosis / genetics
-
Fibrosis / metabolism
-
Gene Expression Regulation / genetics
-
Heart Injuries / metabolism*
-
Integrins / antagonists & inhibitors
-
Integrins / genetics
-
Integrins / metabolism
-
Isoproterenol / pharmacology
-
Male
-
Mechanotransduction, Cellular / genetics
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Microscopy, Atomic Force / instrumentation
-
Microscopy, Electron, Transmission
-
Myocardial Contraction / drug effects
-
Myocardial Contraction / genetics*
-
Myofibroblasts / cytology
-
Myofibroblasts / metabolism*
-
Myofibroblasts / pathology
-
Myofibroblasts / ultrastructure
-
Principal Component Analysis
-
Proteomics
-
RNA-Seq
-
Single-Cell Analysis
Substances
-
COL3A1 protein, mouse
-
Collagen Type I
-
Collagen Type I, alpha 1 Chain
-
Collagen Type III
-
Collagen Type V
-
Integrins
-
Isoproterenol