Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Cell-specific ablation of Hsp47 defines the collagen-producing cells in the injured heart
Hadi Khalil, … , Kazuhiro Nagata, Jeffery D. Molkentin
Hadi Khalil, … , Kazuhiro Nagata, Jeffery D. Molkentin
Published July 2, 2019
Citation Information: JCI Insight. 2019;4(15):e128722. https://doi.org/10.1172/jci.insight.128722.
View: Text | PDF
Research Article Cardiology

Cell-specific ablation of Hsp47 defines the collagen-producing cells in the injured heart

  • Text
  • PDF
Abstract

Collagen production in the adult heart is thought to be regulated by the fibroblast, although cardiomyocytes and endothelial cells also express multiple collagen mRNAs. Molecular chaperones are required for procollagen biosynthesis, including heat shock protein 47 (Hsp47). To determine the cell types critically involved in cardiac injury–induced fibrosis the Hsp47 gene was deleted in cardiomyocytes, endothelial cells, or myofibroblasts. Deletion of Hsp47 from cardiomyocytes during embryonic development or adult stages, or deletion from adult endothelial cells, did not affect cardiac fibrosis after pressure overload injury. However, myofibroblast-specific ablation of Hsp47 blocked fibrosis and deposition of collagens type I, III, and V following pressure overload as well as significantly reduced cardiac hypertrophy. Fibroblast-specific Hsp47-deleted mice showed lethality after myocardial infarction injury, with ineffective scar formation and ventricular wall rupture. Similarly, only myofibroblast-specific deletion of Hsp47 reduced fibrosis and disease in skeletal muscle in a mouse model of muscular dystrophy. Mechanistically, deletion of Hsp47 from myofibroblasts reduced mRNA expression of fibrillar collagens and attenuated their proliferation in the heart without affecting paracrine secretory activity of these cells. The results show that myofibroblasts are the primary mediators of tissue fibrosis and scar formation in the injured adult heart, which unexpectedly affects cardiomyocyte hypertrophy.

Authors

Hadi Khalil, Onur Kanisicak, Ronald J. Vagnozzi, Anne Katrine Johansen, Bryan D. Maliken, Vikram Prasad, Justin G. Boyer, Matthew J. Brody, Tobias Schips, Katja K. Kilian, Robert N. Correll, Kunito Kawasaki, Kazuhiro Nagata, Jeffery D. Molkentin

×

Figure 4

Myofibroblast-specific but not myofiber-specific deletion of Hsp47 in skeletal muscle reduces muscular dystrophy–dependent tissue fibrosis.

Options: View larger image (or click on image) Download as PowerPoint
Myofibroblast-specific but not myofiber-specific deletion of Hsp47 in sk...
(A) Schematic of the MCM cDNA driven by the human skeletal α-actin promoter (myofiber-specific) or the myofibroblast-specific Postn genetic locus to delete the Hsp47 gene with tamoxifen treatment. These lines were crossed into the δ-sarcoglycan–null (Sgcd–/–) background. (B) Experimental tamoxifen dosing regimen administered in the feed. (C) Western blot analysis for total Hsp47 protein using whole muscle protein lysates from the quadriceps of mice of the indicated genotypes. n = 6 mice per group. Gapdh is shown as a loading control. (D) Representative Picrosirius red–stained histological sections from quadriceps and diaphragm from 4-month-old mice of the indicated genotypes. Scale bar: 200 μm. (E and F) Quantitation of fibrosis from Picrosirius red–stained histological sections from quadriceps and diaphragm of 4-month-old mice of the indicated genotypes. n = 7 mice in each group. (G) Average time spent running on a treadmill of 4-month-old mice of the indicated genotypes. n = 6–10 in each group. Significance was determined using P values calculated by 1-way ANOVA with Tukey’s post hoc test. *P < 0.05 versus Sgcd–/–-control. #P < 0.05 versus Sgcd–/– Hsp47fl/fl-Ska-MCM. The legend applies to E, F and G.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts