Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy

Jayasankar, Vasant; Woo, Y. Joseph; Bish, Lawrence T.; Pirolli, Timothy J.; Berry, Mark F.; Burdick, Jeffrey; Bhalla, Ramesh C.; Sharma, Ram V.; Gardner, Timothy J.; Sweeney, H. Lee

doi:10.1161/01.cir.0000138946.29375.49

Cited by 47 publications

(39 citation statements)

References 32 publications

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“…22 Conversely, adenovirus-mediated expression of TIMP-1 was reported to mitigate the severity of ischemic injury. 39 These data suggested that TIMP-1 might exert a protective effect in the myocardium, consistent with the concept that increased MMP activity is a key process driving myocardial pathology after myocardial infarction or stress-related injuries 13,32 ; by this reasoning, expression of TIMP-1 is a physiological response that counterbalances MMP proteolysis, 14,40,41 and TIMP-1 blockade should, in theory, exacerbate disease. We show here that TIMP-1 expression in the heart increases during viral myocarditis, consistent with many studies that show that TIMP-1 is up-regulated in response to myocardial injury.…”

Section: Discussionsupporting

confidence: 72%

Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

Crocker

Frausto

Whitmire

et al. 2007

The American Journal of Pathology

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Coxsackievirus B3 (CVB3) is a major cause of acute myocarditis, a serious condition that is refractory to treatment. Myocardial damage results in tissue remodeling that, if too extensive, may contribute to disease. Remodeling is achieved by extracellular proteolysis mediated by the matrix metalloproteinases (MMPs), and MMP activity is counterbalanced by tissue inhibitors of MMPs (TIMPs). We show herein that TIMP-1 expression is induced in the myocardium by CVB3 infection. Surprisingly, TIMP-1 knockout mice exhibited a profound attenuation of myocarditis, with increased survival. The amelioration of disease in TIMP-1 knockout mice was not attributable to either an altered T-cell response to the virus or to reduced viral replication. These data led us to propose a novel function for TIMP-1: its highly localized upregulation might arrest the MMP-dependent migration of inflammatory cells at sites of infection, thereby anatomically focusing the adaptive immune response. The benefits of TIMP-1 blockade in treating viral myocarditis were confirmed by administering, to wild-type animals, TIMP-1-specific siRNA or polyclonal antisera, both of which diminished CVB3-induced myocarditis. These unexpected findings indicate that increased TIMP-1 expression exacerbates, rather than ameliorates, CVB3-induced myocarditis and, thus, that TIMP-1 may represent a target for the treatment of virus-induced heart disease. (Am J Pathol

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Section: Discussionsupporting

confidence: 72%

Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

Crocker

Frausto

Whitmire

et al. 2007

The American Journal of Pathology

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“…Selective inhibition of TIMP-1 in TIMP-1 knockout mice has also been shown to exacerbate left ventricular remodelling after AMI (48). The role of TIMP-1 activity alteration was confirmed by Jayasankar et al (49), who demonstrated that in left coronary artery ligation-induced MI in rats, TIMP-1 gene transfer inhibited MMP activity, and preserved cardiac function and geometry in ischemic cardiomyopathy.…”

Section: Mmp Inhibitors and Ami In Animal Modelsmentioning

confidence: 90%

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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“…For instance, gene transfer of TIMP1 reduced matrix metalloproteinase activity 6 wk after left anterior descending artery occlusion, preserved both systolic and diastolic function, and reduced myocardial fibrosis (407). Overexpression of IB also improved end-diastolic and systolic function after infarction (894).…”

Section: Other Signaling Targetsmentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy

Cited by 47 publications

References 32 publications

Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

Matrix metalloproteinases and myocardial infarction

Designing Heart Performance by Gene Transfer

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