Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice

Matsumura, Shin-ichiro; Iwanaga, Shiro; Mochizuki, Satsuki; Okamoto, Hiroyuki; Ogawa, Seishi; Okada, Yasunori

doi:10.1172/jci200522304

Cited by 95 publications

(151 citation statements)

References 38 publications

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“…Our previous study 10 and a recent study by Matsumura et al 22 have demonstrated that the inhibition of MMP 2 activity improves the survival rate after acute MI by preventing cardiac rupture and delays after MI remodeling. A recent study by Wang et al 23 has shown that cardiac-specific, constitutively active MMP 2 expression leads to impaired contraction and diminished responses to inotropic stimulation, indicating that MMP 2 can directly impair cardiac function in the absence of superimposed injury.…”

Section: Role Of Mmp 2 In Po Hypertrophymentioning

confidence: 74%

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

et al. 2006

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Abstract-Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (nϭ10) and sibling wild-type (WT) mice (nϭ9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.

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Section: Role Of Mmp 2 In Po Hypertrophymentioning

confidence: 74%

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

et al. 2006

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“…The effects of selective MMPi have also been investigated. In a mouse model of MI (18), the administration of MMP-2 selective inhibitor to wild type mice led to a pronounced improvement in their survival rates, as in mice with targeted deletion of the MMP-2 gene, by preventing cardiac rupture, even though no effect on infarct size was observed. Yarbrough et al (51) also demonstrated that the administration of exogenous MMPi to inhibit MMP-2, -3, -9 and -13, but not MMP-1 and -7, may reduce the progression of left ventricular end-diastolic volume after MI.…”

Section: Mmp Inhibitors and Ami In Animal Modelsmentioning

confidence: 99%

“…The nature of collagen in the ECM is determined by the balance between MMPs and TIMPs. The imbalance between MMPs and TIMPs is the major factor responsible for cardiomyocyte and interstitial changes following AMI in the infarcted and remote areas (18)(19)(20).…”

Section: Myocardial Infarction and Mmpsmentioning

confidence: 99%

“…It has been demonstrated that MMP-9 knockout mice had a lower incidence of cardiac rupture, lower left ventricular dilation and less collagen organization at the infarcted site (47). MMP-2 knockout mice also had greater survival after AMI and less left ventricular adverse remodelling (18,46). Selective inhibition of TIMP-1 in TIMP-1 knockout mice has also been shown to exacerbate left ventricular remodelling after AMI (48).…”

Section: Mmp Inhibitors and Ami In Animal Modelsmentioning

confidence: 99%

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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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“…Rats were orally fed with TISAM suspended in 0.5% w/v methylcellulose 400 solution (WAKO) at a dosage of 5 mg/kg/day, according to a previous protocol (19). Rats were sacrificed on day 21 under deep anesthesia, and hearts were removed and analyzed histologically.…”

Section: Treatment Of Eac With Mmp Inhibitorsmentioning

confidence: 99%

Matrix Metalloproteinase (MMP)-9, but Not MMP-2, Is Involved in the Development and Progression of C Protein-Induced Myocarditis and Subsequent Dilated Cardiomyopathy

Matsumoto

Park

Kohyama

2009

The Journal of Immunology

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Repeated or continuous inflammation of the heart is one of the initiation factors for dilated cardiomyopathy (DCM). In previous studies, we established a DCM animal model by immunizing rats with cardiac C protein. In the present study, we analyze the role of matrix metalloproteinases (MMPs) in experimental autoimmune carditis (EAC) and subsequent DCM to elucidate the pathomechanisms of this disease. In this model, inflammation begins ∼9 days after immunization. At that time, MMP activities were detected by in situ zymography. Real-time PCR analysis revealed continuous up-regulation of MMP-2 mRNA from 2 wk and thereafter. MMP-9 mRNA, however, had only a transient increase at 2 wk. Double staining with in situ zymography and cell markers demonstrated that gelatinase (MMP-2 and MMP-9)-expressing cells are infiltrating macrophages during the early stage and cardiomyocytes at later stages. Minocycline, which inhibits MMP-9 activities more strongly than MMP-2, significantly suppressed EAC, but an MMP-2-specific inhibitor, TISAM, did not affect the course of the disease. Furthermore, immunohistochemical examination revealed that minocycline treatment suppressed T cell and macrophage infiltration strongly, whereas TISAM did not. These findings indicate that MMP-9, but not MMP-2, is involved in the pathogenesis of the acute phase of EAC, and further suggest that MMP-9 inhibitors, minocycline and its derivatives, may be useful therapies for EAC and DCM.

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Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice

Cited by 95 publications

References 38 publications

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

Matrix metalloproteinases and myocardial infarction

Matrix Metalloproteinase (MMP)-9, but Not MMP-2, Is Involved in the Development and Progression of C Protein-Induced Myocarditis and Subsequent Dilated Cardiomyopathy

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