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J Mol Cell Cardiol. 2016 Mar;92:1-9. doi: 10.1016/j.yjmcc.2016.01.019. Epub 2016 Jan 22.

Increased fibroblast chymase production mediates procollagen autophagic digestion in volume overload.

Author information

1
Birmingham Veteran Affairs Medical Center, University of Alabama at Birmingham, Birmingham, AL, United States; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States.
2
Birmingham Veteran Affairs Medical Center, University of Alabama at Birmingham, Birmingham, AL, United States; Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
3
Birmingham Veteran Affairs Medical Center, University of Alabama at Birmingham, Birmingham, AL, United States.
4
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
5
Division of Surgical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
6
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States.
7
Birmingham Veteran Affairs Medical Center, University of Alabama at Birmingham, Birmingham, AL, United States; Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States. Electronic address: louis.dellitalia@va.gov.

Abstract

BACKGROUND:

Previous work has identified mast cells as the major source of chymase largely associated with a profibrotic phenotype. We recently reported increased fibroblast autophagic procollagen degradation in a rat model of pure volume overload (VO). Here we demonstrate a connection between increased fibroblast chymase production and autophagic digestion of procollagen in the pure VO of aortocaval fistula (ACF) in the rat.

METHODS AND RESULTS:

Isolated LV fibroblasts taken from 4 and 12week ACF Sprague-Dawley rats have significant increases in chymase mRNA and chymase activity. Increased intracellular chymase protein is documented by immunocytochemistry in the ACF fibroblasts compared to cells obtained from age-matched sham rats. To implicate VO as a stimulus for chymase production, we show that isolated adult rat LV fibroblasts subjected to 24h of 20% cyclical stretch induces chymase mRNA and protein production. Exogenous chymase treatment of control isolated adult cardiac fibroblasts demonstrates that chymase is internalized through a dynamin-dependent mechanism. Chymase treatment leads to an increased formation of autophagic vacuoles, LC3-II production, autophagic flux, resulting in increased procollagen degradation. Chymase inhibitor treatment reduces cyclical stretch-induced autophagy in isolated cardiac fibroblasts, demonstrating chymase's role in autophagy induction.

CONCLUSION:

In a pure VO model, chymase produced in adult cardiac fibroblasts leads to autophagic degradation of newly synthesized intracellular procollagen I, suggesting a new role of chymase in extracellular matrix degradation.

KEYWORDS:

Autophagy; Cardiac fibroblast; Chymase; Intracellular procollagen; Volume overload

PMID:
26807691
PMCID:
PMC5198899
DOI:
10.1016/j.yjmcc.2016.01.019
[Indexed for MEDLINE]
Free PMC Article
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