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Am J Physiol Heart Circ Physiol. 2018 Jul 1;315(1):H92-H100. doi: 10.1152/ajpheart.00719.2017. Epub 2018 Mar 9.

Increased macrophage-derived SPARC precedes collagen deposition in myocardial fibrosis.

Author information

1
Department of Pathology and Laboratory Medicine, Medical University of South Carolina , Charleston, South Carolina.
2
Ralph H. Johnson Department of Veterans Affairs Medical Center , Charleston, South Carolina.
3
Division of Cardiology, Department of Medicine, Medical University of South Carolina , Charleston, South Carolina.
4
Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.

Abstract

Myocardial fibrosis and the resultant increases in left ventricular stiffness represent pivotal consequences of chronic pressure overload (PO) that impact both functional capacity and the rates of morbid and mortal events. However, the time course and cellular mechanisms that underlie PO-induced fibrosis have not been completely defined. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that has been shown to be required for insoluble collagen deposition and increased myocardial stiffness in response to PO in mice. As macrophages are associated with increases in fibrillar collagen, the hypothesis that macrophages represent a source of increased SPARC production in the PO myocardium was tested. The time course of changes in the myocardial macrophage population was compared with changes in procollagen type I mRNA, production of SPARC, fibrillar collagen accumulation, and diastolic stiffness. In PO hearts, mRNA encoding collagen type I was increased at 3 days, whereas increases in levels of total collagen protein did not occur until 1 wk and were followed by increases in insoluble collagen at 2 wk. Increases in muscle stiffness were not detected before increases in insoluble collagen content (>1 wk). Significant increases in myocardial macrophages that coincided with increased SPARC were found but did not coincide with increases in mRNA encoding collagen type I. Furthermore, immunohistochemistry and flow cytometry identified macrophages as a cellular source of SPARC. We conclude that myocardial macrophages play an important role in the time-dependent increases in SPARC that enhance postsynthetic collagen processing, insoluble collagen content, and myocardial stiffness and contribute to the development of fibrosis. NEW & NOTEWORTHY Myocardial fibrosis and the resultant increases in left ventricular and myocardial stiffness represent pivotal consequences of chronic pressure overload. In this study a murine model of cardiac fibrosis induced by pressure overload was used to establish a time course of collagen expression, collagen deposition, and cardiac macrophage expansion.

KEYWORDS:

collagen; extracellular matrix; matricellular proteins; postsynthetic collagen processing; secreted protein acidic and rich in cysteine

PMID:
29522370
PMCID:
PMC6087775
DOI:
10.1152/ajpheart.00719.2017
[Indexed for MEDLINE]
Free PMC Article

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