Matrix Metalloproteinases: Drug Targets for Myocardial Infarction

Yabluchanskiy, Andriy; Li, Yaojun; Chilton, Robert; Lindsey, Merry L.

doi:10.2174/1389450111314030002

Cited by 29 publications

(27 citation statements)

References 148 publications

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“…At 8 weeks, there were no detectable differences in gene expression of tumor necrosis factor alpha, IL1β, IL6, IL12α, and interferon-γ associated with inflammation; this is not unexpected because these cytokines are upregulated acutely following MI (29). We also measured expression of genes involved in tissue remodeling in MI, including MMP-2, -9, -12, -14 and tissue inhibitor of metalloproteinase-1 (30). Differences in MMP-2 and -12 could be detected at 8 weeks following AAVAng-(1-9) delivery, suggesting one possible mechanism by which Ang-(1-9) can modulate remodeling during scar evolution.…”

Section: Discussionmentioning

confidence: 93%

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Fattah

Nather

McCarroll

et al. 2016

Journal of the American College of Cardiology

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BackgroundAngiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI).ObjectivesThe authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction.MethodsC57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model.ResultsGene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end-systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A–dependent mechanism.ConclusionsOur novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A–dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI.

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Section: Discussionmentioning

confidence: 93%

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Fattah

Nather

McCarroll

et al. 2016

Journal of the American College of Cardiology

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“…Indeed, several mouse models of MMP over-expression have shown adverse LV remodeling and increased mortality [86,87]. As such, modulation of MMPs, or their inhibitors—mainly TIMPs 1 and 2—is a possible avenue for post-MI therapy [88] and may reduce arrhythmogenesis by limiting interstitial fibrosis. Furthermore, MMPs degrade connexins [52], thus MMP inhibition may improve cell-cell coupling and conduction.…”

Section: Post-mi Arrhythmia Preventionmentioning

confidence: 99%

“…As a note of caution, MMPs are widespread and expressed in most tissues and broad-spectrum MMP inhibitors have been unsuccessful in clinical trials due to musculoskeletal toxicity. Thus, therapeutics with affinities for specific MMPs may prove more beneficial [88]. For more discussion on MMP roles in post-MI remodeling, see Lindsey et al .…”

Section: Post-mi Arrhythmia Preventionmentioning

confidence: 99%

The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction

Stuart

Jesus

Lindsey

et al. 2016

Journal of Molecular and Cellular Cardiology

192

113

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Optimal healing of damaged tissue following myocardial infarction (MI) requires a coordinated cellular response that can be divided into three phases: inflammatory, proliferative/reparative, and maturation. The inflammatory phase, characterized by rapid influx of cytokines, chemokines, and immune cells, is critical to the removal of damaged tissue. The onset of the proliferative/reparative phase is marked by increased proliferation of myofibroblasts and secretion of collagen to replace dead tissue. Lastly, crosslinking of collagen fibers and apoptosis of immune cells marks the maturation phase. Excessive inflammation or fibrosis has been linked to increased incidence of arrhythmia and other MI-related pathologies. This review describes the roles of inflammation and fibrosis in arrhythmogenesis and prospective therapies for anti-arrhythmic treatment.

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“…MMP-9 deletion attenuates LV dysfunction and collagen deposition and promotes angiogenesis post-MI in mice [70,71]. Neutrophil-derived MMP-9 may exert very early effects in the MI setting by degrading extracellular matrix and promoting leukocyte cell infiltration into the infarct area, while MMP-9 from other cells may regulate scar formation [72,73]. …”

Section: Reviewmentioning

confidence: 99%

Neutrophil roles in left ventricular remodeling following myocardial infarction

Yabluchanskiy

Lindsey

2013

Fibrogenesis Tissue Repair

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163

121

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Polymorphonuclear granulocytes (PMNs; neutrophils) serve as key effector cells in the innate immune system and provide the first line of defense against invading microorganisms. In addition to producing inflammatory cytokines and chemokines and undergoing a respiratory burst that stimulates the release of reactive oxygen species, PMNs also degranulate to release components that kill pathogens. Recently, neutrophil extracellular traps have been shown to be an alternative way to trap microorganisms and contain infection. PMN-derived granule components are also involved in multiple non-infectious inflammatory processes, including the response to myocardial infarction (MI). In this review, we will discuss the biological characteristics, recruitment, activation, and removal of PMNs, as well as the roles of PMN-derived granule proteins in inflammation and innate immunity, focusing on the MI setting when applicable. We also discuss future perspectives that will direct research in PMN biology.

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Matrix Metalloproteinases: Drug Targets for Myocardial Infarction

Cited by 29 publications

References 148 publications

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction

Neutrophil roles in left ventricular remodeling following myocardial infarction

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