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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.
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Research Article Cardiology

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

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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

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Figure 5

Myofibroblast-specific Hsp47 deletion alters acute scar formation and the hypertrophic response.

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Myofibroblast-specific Hsp47 deletion alters acute scar formation and th...
(A) Experimental scheme whereby αMHC-MerCreMer–transgenic mice or Postn-MerCreMer allele–containing mice were subjected to myocardial infarction injury for 4 weeks with 2 injections (vertical red arrows) of tamoxifen treatment and then tamoxifen in the feed for 4 weeks (horizontal red arrow). (B) Kaplan-Meier plot of survival of the indicated genotypes of mice after MI injury. n = 11–13 mice in each group. (C) Quantitation of fibrosis from Picrosirius red–stained histological sections from hearts after 4 week of I/R injury of the indicated genotypes. n = 6 mice in each group. (D) Gravimetric assessed heart-weight-to-body-weight (HW/BW) ratios in mice of the indicated genotypes after 4 weeks of TAC. n = 5 sham mice, n = 9–10 TAC mice in each group. *P < 0.05 versus sham; #P < 0.05 versus Postn-MCM TAC. P values were calculated by 2-way ANOVA and Bonferroni post hoc test. (E–G) Echocardiographic assessment of ventricular (LV) calculated mass, left ventricular fractional shortening (FS%) percentage, and early mitral inflow velocity to mitral annular early diastolic velocity ratio (E/e) in the indicated genotypes of mice after 4 weeks of TAC injury or a sham procedure. *P < 0.05 versus Postn-MCM sham. #P < 0.05 versus Postn-MCM TAC. P values were calculated with 1-way ANOVA with Tukey’s post hoc test. Number of mice used is shown in the scatter plots.

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