Assigning matrix metalloproteinase roles in ischaemic cardiac remodelling

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Abstract

<p class="first" id="P1">Matrix metalloproteinases (MMPs) and their endogenous inhibitors have been studied in the myocardium for the past 2 decades. An incomplete knowledge base and experimental design issues with inhibitors have hampered attempts at translation, but clinical interest remains high because of strong associations between MMPs and outcomes after myocardial infarction (MI) as well as mechanistic studies showing MMP involvement at multiple stages of the MI wound-healing process. This Review focuses on how our understanding of MMPs has evolved from a one-dimensional early focus on measuring MMP activity, monitoring MMP:inhibitor ratios, and evaluating one MMP–substrate pair to the current use of systems biology approaches to integrate the whole MMP repertoire of roles in the left ventricular response to MI. MMP9 is used as an example MMP to explain these concepts and to provide a template for examining MMPs as mechanistic mediators of cardiac remodelling. </p>

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The inflammatory response in myocardial injury, repair, and remodelling.

Nikolaos G Frangogiannis (2014)

Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.

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Circulating Noncoding RNAs as Biomarkers of Cardiovascular Disease and Injury.

Janika Viereck, Thomas Thum (2017)

The discovery of thousands of noncoding RNAs (ncRNAs) has expanded our view on mammalian genomes and transcriptomes, as well as their organization and regulation. Accumulating evidence on aberrantly regulated ncRNAs, including short microRNAs, long ncRNAs and circular RNAs, across various heart diseases indicates that ncRNAs are critical contributors to cardiovascular pathophysiology. In addition, ncRNAs are released into the circulation where they are present in concentration levels that differ between healthy subjects and diseased patients. Although little is known about the origin and function of such circulating ncRNAs, these molecules are increasingly recognized as noninvasive and readily accessible biomarker for risk stratification, diagnosis and prognosis of cardiac injury, and multiple forms of cardiovascular disease. In this review, we summarize recent findings on biological characteristics of circulating ncRNAs and highlight their value as potential biomarker in selected pathologies of cardiovascular disease.

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Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease.

Odette Poirier, Christoph Bickel, Jürgen Meyer … (2003)

Matrix metalloproteinase (MMP)-9 secretion by macrophages and other inflammatory cells accelerates atherosclerotic progression and destabilizes vulnerable plaque in animal models. However, epidemiological data evaluating the prognostic impact of circulating concentrations and functional genetic variations of MMP-9 are lacking. In a prospective study of 1127 patients with documented coronary artery disease, we measured baseline plasma MMP-9 levels and determined the MMP-9/C-1562T and MMP-9/R279Q genotypes. During the follow-up period (mean of 4.1 years), 97 patients died from cardiovascular (CV) causes. Median concentrations of MMP-9 were significantly higher among patients who experienced a fatal CV event than among those who did not (62.2 versus 47.8 ng/mL; P<0.0001). The crude hazard risk ratio of CV death associated with increasing quartiles of MMP-9 was 1.4 (95% CI, 1.2 to 1.8; P<0.0001), and after adjustment for clinical and therapeutic confounders, it was 1.3 (95% CI, 1.1 to 1.6; P=0.005). Additional adjustment for highly sensitive CRP, interleukin-6, fibrinogen, and interleukin-18 revealed a hazard risk ratio to 1.2 (95% CI, 0.9 to 1.6; P=0.15). The T allele of the C-1562T polymorphism was associated with increased MMP-9 levels in a fairly codominant fashion (P=0.004). Although none of the polymorphisms was significantly related with future CV death, there was a significant association (P=0.02) between the R279Q polymorphism and CV events in patients with stable angina. Plasma MMP-9 concentration was identified as a novel predictor of CV mortality in patients with coronary artery disease. Whether it provides independent prognostic information compared with other inflammatory markers will have to be additionally assessed.