Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling

Lindsey, Merry L.; Iyer, Rugmani Padmanabhan; Jung, Mira; DeLeon‐Pennell, Kristine Y.; Ma, Yonggang

doi:10.1016/j.yjmcc.2015.12.018

Cited by 95 publications

(79 citation statements)

References 91 publications

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“…We also assumed that like most enzymatic reactions, the rate of collagen degradation depends on the product of the concentration of active enzyme (MMP expression and activity rise quickly and peak just a few days after MI in rodents [79–82]) and the concentration of substrate. Clearly, this simple model omits many aspects of MMP biology that could also produce counter-intuitive effects on overall collagen content, such as changes in degradation of other ECM components that influence collagen assembly or in the generation of peptides that influence fibrosis-related signaling [83]. Nevertheless, this simple model matched collagen area fraction data from healing rat infarcts well (Figure 4), and predicted that even 75% inhibition of MMP activity would not produce a detectable change in collagen area fraction for at least the first 3–4 weeks.…”

Section: Modifying Infarct Mechanical Propertiesmentioning

confidence: 99%

Modifying the mechanics of healing infarcts: Is better the enemy of good?

Clarke

Richardson

Holmes

2016

Journal of Molecular and Cellular Cardiology

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Myocardial infarction (MI) is a major source of morbidity and mortality worldwide, with over 7 million people suffering infarctions each year. Heart muscle damaged during MI is replaced by a collagenous scar over a period of several weeks, and the mechanical properties of that scar tissue are a key determinant of serious post-MI complications such as infarct rupture, depression of heart function, and progression to heart failure. Thus, there is increasing interest in developing therapies that modify the structure and mechanics of healing infarct scar. Yet most prior attempts at therapeutic scar modification have failed, some catastrophically. This article reviews available information about the mechanics of healing infarct scar and the functional impact of scar mechanical properties, and attempts to infer principles that can better guide future attempts to modify scar. One important conclusion is that collagen structure, mechanics, and remodeling of healing infarct scar vary so widely among experimental models that any novel therapy should be tested across a range of species, infarct locations, and reperfusion protocols. Another lesson from past work is that the biology and mechanics of healing infarcts are sufficiently complex that the effects of interventions are often counterintuitive; for example, increasing infarct stiffness has little effect on heart function, and inhibition of matrix metalloproteases (MMPs) has little effect on scar collagen content. Computational models can help explain such counterintuitive results, and are becoming an increasingly important tool for integrating known information to better identify promising therapies and design experiments to test them. Moving forward, potentially exciting new opportunities for therapeutic modification of infarct mechanics include modulating anisotropy and promoting scar compaction.

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Section: Modifying Infarct Mechanical Propertiesmentioning

confidence: 99%

Modifying the mechanics of healing infarcts: Is better the enemy of good?

Clarke

Richardson

Holmes

2016

Journal of Molecular and Cellular Cardiology

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“…Nonetheless, the post-MI activation of other mechanisms, such as the renin-angiotensin-aldosterone system or metalloproteinase may have been at play in the cytokine response and were not affected by LDE-MTX. 36,37 Fibrosis has a major role in repairing the damaged myocardium, but excess and deregulated fibrosis may contribute to pathological cardiac remodeling. 38 In this respect, LDE-MTX treatment led to a reduction in fibrosis in both subendocardial and interstitial areas, as documented by the local reduction of collagen I and III.…”

mentioning

confidence: 99%

Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

Maranhão¹,

Guido²,

Lima³

et al. 2017

IJN

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Purpose Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment. Materials and methods Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham-surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy. Results LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of commercial MTX were minor, and did not improve LV function or infarction size. Both treatments did not induce any toxicity. Conclusion The remarkable improvement in heart function and reduction in infarction size achieved by LDE-MTX supports future clinical trials.

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“…Interestingly, treatment of mice with a synthetic peptide mimicking the endogenous matricryptin (p1159/59) after MI attenuated LV dilation and preserved LV structure [220]. Further discussion on how MMPs act as an input and output signals for post-myocardial remodeling is reviewed by Dr. Lindsay and colleagues [221]. …”

Section: Ecm-cell Interactions In the Injured Myocardiummentioning

confidence: 99%

Extracellular matrix-mediated cellular communication in the heart

Valiente-Alandí

Schafer

Blaxall

2016

Journal of Molecular and Cellular Cardiology

128

107

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The extracellular matrix (ECM) is a complex and dynamic scaffold that maintains tissue structure and dynamics. However, the view of the ECM as an inert architectural support has been increasingly challenged. The ECM is a vibrant meshwork, a crucial organizer of cellular microenvironments. It plays a direct role in cellular interactions regulating cell growth, survival, spreading, proliferation, differentiation and migration through the intricate relationship among cellular and acellular tissue components. This complex interrelationship preserves cardiac function during homeostasis; however it is also responsible for pathologic remodeling following myocardial injury. Therefore, enhancing our understanding of this cross-talk may provide mechanistic insights into the pathogenesis of heart failure and suggest new approaches to novel, targeted pharmacologic therapies. This review explores the implications of ECM-cell interactions in myocardial cell behavior and cardiac function at baseline and following myocardial injury.

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Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling

Cited by 95 publications

References 91 publications

Modifying the mechanics of healing infarcts: Is better the enemy of good?

Modifying the mechanics of healing infarcts: Is better the enemy of good?

Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

Extracellular matrix-mediated cellular communication in the heart

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