A role for decorin in the remodeling of myocardial infarction
Introduction
In myocardial infarction, the regulation of collagen fibrillogenesis, synthesis, and degradation can be altered leading to disorganized collagen fibers, rupture of collagen struts, myocyte slippage, and ultimately thinning or bulging of the infarct zone (Cleutjens et al., 1995, Holmes et al., 1994, Weber, 1989). Although collagen metabolism has been a common subject of research, mechanisms controlling collagen fiber assembly and structural integrity during infarct scar formation and wound healing remain poorly understood.
Healing and ventricular remodeling are dynamic processes that progress in parallel. During the early phase of ischemic injury, myocardial restructuring depends on a balance between extracellular matrix synthesis and degradation. The structural integrity and stiffness of the infarct scar depends on collagen content, crosslinking, and orientation (Holmes et al., 1997, Kawaguchi and Kitabatake, 1995), and uncoordinated restructuring may lead to infarct expansion, aneurysm, ventricular dilatation, tissue damage, and impaired pump function (Jugdutt et al., 1997, Weber et al., 1994). In response to ischemic injury, the myocardial collagen matrix is rapidly and severely damaged (Zhao et al., 1987), due to increased activities of collagenase and other proteinases (Takahashi et al., 1990).
Collagen fiber formation in vitro occurs by self-assembly of procollagen α-chains into a triple-helical collagen molecule, groups of which organize to form the quarter-stagger array of a collagen fibril. But, the complex in vivo situation may involve factors which may assist or regulate in vivo fibrillogenesis, including thrombospondin-2 (Kyriakides et al., 1998), fibromodulin (Scott, 1996), osteopontin (Liaw et al., 1998), lumican (Scott, 1996), and decorin (Weber et al., 1996).
Decorin is a ubiquitous chondroitin/dermatan sulfate proteoglycan, associated with all major type I and II collagen-rich tissues (Bianco et al., 1990) and co-localizes with large helical collagen fibers (Thieszen and Rosenquist, 1995). Decorin is thought to bind to specific sites on collagen molecules as they assemble to prevent lateral association and thus may be responsible for collagen fibril diameter uniformity (Weber et al., 1996). The binding site of decorin on type I collagen was identified near the C-terminus of type I collagen, very close to one of the major intermolecular crosslinking sites of collagen heterotrimers (Keene et al., 2000). In addition, decorin incorporation has been shown to increase ultimate tensile strength of uncrosslinked collagen fibers in vitro (Pins et al., 1997). Thus, decorin could affect diameter uniformity, crosslinking, and mechanical properties of collagen fibrils.
A mouse model for null-expression of decorin displays non-uniformity of connective tissue collagen fiber diameter, abnormal collagen organization, and skin fragility (Danielson et al., 1997). Collagen fibril uniformity may play an even more prominent role during wound healing. In this study, we tested the hypothesis that decorin deficiency alters scar structure, mechanics, and ventricular remodeling following experimentally-induced myocardial infarction in mice. Overall, our results support the notion that the defects in collagen fibril organization in decorin-null mice create a scar with inferior mechanical properties which is prone to expansion and thinning, thereby contributing to increased remote hypertrophy and ventricular dilatation.
Section snippets
Decorin deficiency does not alter collagen concentration or crosslinking
The amount of collagen accumulation and extent of collagen crosslinking following MI could represent a major determinant of ventricular remodeling. To determine whether decorin deficiency affects collagen biochemistry following MI, we evaluated ventricular collagen amount (hydroxyproline concentration) and crosslink density (mol pyridoxamine per mol collagen) 14 days following permanent MI. Surprisingly, we detected no physiologically relevant difference in total LV collagen between genotypes (
Discussion
Here, we tested the hypothesis that decorin deficiency alters post-MI scar structure and ventricular remodeling following experimentally-induced myocardial infarction in mice. In mature scar from decorin-null mice, we measured non-uniform collagen fibril diameters, abnormal fibril organization, and loose fibril packing compared with wildtype. Fibrosis of remote noninfarcted myocardium was not different between genotypes, nor was collagen concentration or crosslinking altered due to decorin
Mouse background and genotyping
The decorin-null mouse (Dcn− / −) and wildtype control littermates (Dcn+ / +) are maintained on a 129Sv X B1/Swiss mixed background, and was developed previously by one of us (Danielson et al., 1997). A PCR technique was used to determine genotype as described previously (Danielson et al., 1997).
Chronic surgery
All studies were performed according to NIH ILAR Guide for the Care and Use of Laboratory Animals, and all experimental protocols were reviewed and approved by the UCSD Animal Subjects Committee. All mice
Acknowledgements
Fred Harwood and Dr. David Amiel provided collagen biochemistry analysis. Zhuangjie Li provided technical assistance. Support received from the American Heart Association (Predoctoral Fellowship, SM Weis), the National Science Foundation (BES 0086482, AD McCulloch), the National Institutes of Health (5 PO1 HL46345-12, AD McCulloch; HL43617, JW Covell; CA39481 and CA47282 RV Iozzo), and the National Center for Microscopy and Imaging Research (PHS RR04050).
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