Region- and Type-Specific Induction of Matrix Metalloproteinases in Post–Myocardial Infarction Remodeling

Wilson, Eric; Moainie, Sina L.; Baskin, Julia M.; Lowry, Abigail S.; Deschamps, Anne M.; Mukherjee, Rupak; Guy, T. Sloane; John-Sutton, Martin G. St.; Gorman, Joseph H.; Edmunds, L. Henry; Gorman, Robert C.; Spinale, Francis G.

doi:10.1161/01.cir.0000068375.40887.fa

Cited by 191 publications

(246 citation statements)

References 33 publications

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“…Several enzymes are capable of mediating this cleavage, and several, including MMP-8, MMP-13, and MMP-14, are expressed after myocardial infarction. 8,27,28 Thus, Col1a1 r/r mice constitute a powerful tool for elucidating the role of collagen degradation during infarct healing, and their use circumvents compensation or redundancy among collagen-degrading enzymes. In addition, collagenases can have targets other than type I collagen.…”

Section: Discussionmentioning

confidence: 99%

Type I Collagen Cleavage Is Essential for Effective Fibrotic Repair after Myocardial Infarction

Zhang

O’Neil

Lei

et al. 2011

The American Journal of Pathology

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Efficient deposition of type I collagen is fundamental to healing after myocardial infarction. Whether there is also a role for cleavage of type I collagen in infarct healing is unknown. To test this, we undertook coronary artery occlusion in mice with a targeted mutation (Col1a1 r/r ) that yields collagenase-resistant type I collagen. Eleven days after infarction, Col1a1 r/r mice had a lower mean arterial pressure and peak left ventricular systolic pressure, reduced ventricular systolic function, and worse diastolic function, compared with wild-type littermates. Infarcted Col1a1 r/r mice also had greater 30-day mortality, larger left ventricular lumens, and thinner infarct walls. Interestingly, the collagen fibril content within infarcts of mutant mice was not increased. However, circular polarization microscopy revealed impaired collagen fibril organization and mechanical testing indicated a predisposition to scar microdisruption. Three-dimensional lattices of collagenase-resistant fibrils underwent cell-mediated contraction, but the fibrils did not organize into birefringent collagen bundles. In addition, time-lapse microscopy revealed that, although cells migrated smoothly on wild-type collagen fibrils, crawling and repositioning on collagenase-resistant collagen was impaired. We conclude that type I collagen cleavage is required for efficient healing of myocardial infarcts and is critical for both dynamic positioning of collagen-producing cells and hierarchical assembly of collagen fibrils. This seemingly paradoxical requirement for collagen cleavage in fibrotic repair should be considered when designing potential strategies to inhibit matrix degradation in cardiac disease. Rapid deposition of type I collagen is critical to cardiac repair after myocardial infarction. When effectively elaborated, a type I collagen-rich matrix provides a mechanically strong network that maintains cardiac integrity, minimizes infarct expansion, and resists maladaptive remodeling.1 Elaboration of type I collagen is a multistep process that includes expression of the genes encoding pro-␣1(I) and pro-␣2(I) collagen chains, intracellular winding of the chains, and secretion of type I procollagen. Outside the cell, the propeptide termini are cleaved and the resulting triple helical type I collagen assembles into fibrils, which then cross-link and pack. Collagen deposition can be opposed by processes that degrade type I collagen. Enzymes that destroy the integrity of type I collagen by cleaving the triple helical domain are important in this regard. These include the interstitial collagenases, matrix metalloproteinase (MMP)Ϫ1, MMP-8, and MMP-13, that cleave type I collagen three fourths along the length of its triple helix. Broader-spectrum MMPs, such as MMP-2 and membrane-type (MT)1-MMP/MMP-14, also have the capacity to cleave native type I collagen.3,4 Several studies have highlighted the potential for interstitial collagenases to adversely affect the heart. Transgenic expression of MMP-1 promotes ventricular dilatation and dysfun...

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Section: Discussionmentioning

confidence: 99%

Type I Collagen Cleavage Is Essential for Effective Fibrotic Repair after Myocardial Infarction

Zhang

O’Neil

Lei

et al. 2011

The American Journal of Pathology

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“…The study also demonstrated that MMP-9, which increased in the myocardium, was leukocyte-derived. From a large animal study (24), AMI was induced in sheep, and the tissue levels of MMPs and TIMPs were studied at eight weeks. Wilson et al (24) found that the region-and type-specific changes in MMPs occurred after MI.…”

Section: Myocardial Infarction and Mmpsmentioning

confidence: 99%

Matrix metalloproteinases and myocardial infarction

Phatharajaree

Phrommintikul

Chattipakorn

2007

Canadian Journal of Cardiology

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A cute myocardial infarction (AMI) is one of the most important health problems in many nations around the world. It may be found in many age groups, but is predominant among elderly people (1). The incidence of AMI has been increasing, possibly due to the changes in lifestyle and dietary intake that lead to an increase in coronary risk factors for cardiovascular disease.AMI has devastating consequences in the early phase, such as cardiac rupture, and in the chronic phase, such as chronic heart failure, for which the risk is mainly determined by infarct size (2). Larger infarct size induces gross morphological, histological and molecular changes of the infarcted and noninfarcted regions. These changes are known as the cardiac remodelling process. The degree of cardiac remodelling is closely related to the incidence of cardiac arrhythmias, heart failure and mortality (3). Cardiac remodelling involves changes in cardiac myocytes and in the extracellular matrix (ECM). The ECM contains a wide array of structural proteins, such as fibrillar collagen, proteoglycans and glycosaminoglycans, and serves as a reservoir for biologically active molecules. Because myocardial collagens maintain the structural integrity of adjoining myocytes and provide the means by which myocyte shortening is translated into cardiac pump function, changes in the ECM result in a loss of normal structural and functional myocardium.Matrix metalloproteinase (MMP) is a proteolytic enzyme that has been identified in the myocardium, and is likely to contribute to ECM changes and myocardial remodelling. In the past few decades, growing evidence from basic and clinical studies have demonstrated the important role of MMPs in the progression of left ventricular dimension, remodelling and mortality following AMI. In the present article, MMP expression after AMI and its role as a possible prognostic marker are reviewed. Currently available data regarding the role of MMP inhibitors as a possible novel therapeutic intervention are also discussed. Acute myocardial infarction (AMI) is currently one of the most important health problems in many countries around the world. Following AMI, many cytokines and proteolytic enzymes are released. Among these, matrix metalloproteinases (MMPs) are important proteolytic enzymes that lead to degradation of the extracellular matrix and to changes in cardiomyocytes in both infarcted and noninfarcted myocardium. This process is known as cardiac remodelling. It has been demonstrated that more than one type of MMP is present in the circulation after cardiomyocyte injury. A number of studies have demonstrated the correlations between these MMP levels and the severity of a coronary lesion, the progression of left ventricular dimension and the survival rate following AMI in both animal and human studies. MMPs have also been proposed as a possible novel prognostic indicator for myocardial infarction patients. Although the use of MMP inhibitors to improve cardiac outcome in AMI patients has been investigated, discrepancies in the re...

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“…Studies of mice with a targeted deletion of mmp9 clearly implicate this factor in not only left ventricular dilation but also in inhibition of neo-angiogenesis postinfarct (1,10,15,22,23,38). Other studies suggest MMP13 may also be important in late progression of remodeling (46).…”

mentioning

confidence: 99%

Helix-Loop-Helix Protein p8, a Transcriptional Regulator Required for Cardiomyocyte Hypertrophy and Cardiac Fibroblast Matrix Metalloprotease Induction

Goruppi

Patten

Force

et al. 2007

Molecular and Cellular Biology

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Cardiomyocyte hypertrophy and extracellular matrix remodeling, primarily mediated by inflammatory cytokine-stimulated cardiac fibroblasts, are critical cellular events in cardiac pathology. The molecular components governing these processes remain nebulous, and few genes have been linked to both hypertrophy and matrix remodeling. Here we show that p8, a small stress-inducible basic helix-loop-helix protein, is required for endothelin-and ␣-adrenergic agonist-induced cardiomyocyte hypertrophy and for tumor necrosis factorstimulated induction, in cardiac fibroblasts, of matrix metalloproteases (MMPs) 9 and 13-MMPs linked to general inflammation and to adverse ventricular remodeling in heart failure. In a stimulus-dependent manner, p8 associates with chromatin containing c-Jun and with the cardiomyocyte atrial natriuretic factor (anf) promoter and the cardiac fibroblast mmp9 and mmp13 promoters, established activator protein 1 effectors. p8 is also induced strongly in the failing human heart by a process reversed upon therapeutic intervention. Our results identify an unexpectedly broad involvement for p8 in key cellular events linked to cardiomyocyte hypertrophy and cardiac fibroblast MMP production, both of which occur in heart failure.The progression to heart failure involves an initial phase of pathological cardiomyocyte hypertrophy, which develops as a consequence of excess hemodynamic work load and may be triggered by ␣-adrenergic agents, angiotensin II, and/or endothelin. Pathological cardiomyocyte hypertrophy is followed by left ventricular decompensation, characterized by cardiomyocyte loss, and interstitial fibrosis-direct contributors to adverse ventricular remodeling. Ultimately, the contractile properties of the heart are compromised, resulting in heart failure (17,18,27). The molecular components and cellular events required for heart failure remain incompletely understood, and few genes have been linked to both pathological hypertrophy of cardiomyocytes and matrix remodeling (9,17,18,27).Post-myocardial infarction, in addition to hypertrophy of surviving cardiomyocytes, remodeling of the extracellular matrix occurs, particularly within the territory of the infarct, as lost myocytes are replaced by fibrous tissue (22, 23). Key to this remodeling process is the production and release of matrix metalloproteases (MMPs) from both resident cells, especially cardiac fibroblasts, and infiltrating leukocytes. Inflammatory cytokine production (especially tumor necrosis factor [TNF], interleukin-1 [IL-1], and IL-6 family members) by these cells is believed to be the major trigger for induction of MMP expression.Studies employing broad-spectrum inhibitors of MMPs have shown that cytokine (TNF)-stimulated upregulation of the expression of MMPs is a central factor leading to left ventricular dilation post-myocardial infarction, a harbinger of heart failure (28,32,48). Studies of mice with a targeted deletion of mmp9 clearly implicate this factor in not only left ventricular dilation but also in inhibition of neo-an...

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Region- and Type-Specific Induction of Matrix Metalloproteinases in Post–Myocardial Infarction Remodeling

Cited by 191 publications

References 33 publications

Type I Collagen Cleavage Is Essential for Effective Fibrotic Repair after Myocardial Infarction

Type I Collagen Cleavage Is Essential for Effective Fibrotic Repair after Myocardial Infarction

Matrix metalloproteinases and myocardial infarction

Helix-Loop-Helix Protein p8, a Transcriptional Regulator Required for Cardiomyocyte Hypertrophy and Cardiac Fibroblast Matrix Metalloprotease Induction

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