Extracellular degradative pathways in myocardial remodeling and progression to heart failure

Spinale, Francis G.; Gunasinghe, Himali R.; Sprunger, Philip D.; Baskin, Julia M.; Bradham, William C.

doi:10.1054/jcaf.2002.129259

Cited by 46 publications

(38 citation statements)

References 25 publications

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“…Numerous studies have implicated a direct contribution of MMPs in the pathophysiological dilatation that occurs in the failing heart (22,39). However, the findings here implicate ET-1 in causing the acute stimulation of cardiac mast cellmediated activation of MMPs in chronic volume overload.…”

Section: Mmp Activation Postfistulamentioning

confidence: 46%

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Murray

Gardner²,

Brower³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Murray DB, Gardner JD, Brower GL, Janicki JS. Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cellmediated ventricular remodeling in rats. Am J Physiol Heart Circ Physiol 294: H1251-H1257, 2008. First published January 4, 2008 doi:10.1152/ajpheart.00622.2007.-The objective of this study was to investigate the effect a nonselective endothelin-1 (ET-1) receptor antagonist (bosentan) had on the acute myocardial remodeling process including left ventricular (LV) mast cells and matrix metalloproteinase (MMP) activity secondary to volume overload. Additionally, we investigated the overall functional outcome of preventative endothelin receptor antagonism during 14 days of chronic volume overload. LV tissue from sham-operated (Sham), untreated-fistula (Fist), and bosentan (100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 )-treated animals (Fist ϩ Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction at 1 and 5 days after the creation of an aortocaval fistula. When compared with untreated fistulas, bosentan treatment prevented the marked increase in LV mast cell density at 1 day postfistula (3.1 Ϯ 0.3 vs. 1.3 Ϯ 0.3 LV mast cells/mm 2 , Fist vs. Fist ϩ Bos, P Յ 0.01). Additionally, the substantial increase in MMP-2 activation in the untreated fistula at 1 day was prevented following bosentan treatment (1.6 Ϯ 0.3 vs. 0.9 Ϯ 0.1 arbitrary activity units, Fist vs. Fist ϩ Bos, P Յ 0.01). The marked decrease in collagen volume fraction seen in the Fist group (1.4 Ϯ 0.1 vs. 0.8 Ϯ 0.1% myocardial tissue, Sham vs. Fist, P Յ 0.01) was significantly attenuated following bosentan treatment at both the 1-and 5-day time points. Lastly, a 2-wk preventative treatment with bosentan resulted in significant attenuation of the increase in LV end-systolic and -diastolic volumes compared with those in untreated fistula hearts. In summary, nonselective ET-1 antagonism prevents the acute increases in cardiac mast cell density and MMP activation induced secondary to chronic volume overload. By preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits in the first 2 wk of chronic volume overload. Accordingly, these results are the first to demonstrate that cardiac mast cells are responsive to the endogenous endothelin system in vivo. Another novel finding from this study is that chronic nonspecific endothelin antagonism may inadvertently potentiate ET-1-mediated signaling.bosentan; heart; extracellular matrix; cardiac function DISCOVERED ONLY 16 years ago, the neurohormone endothelin-1 (ET-1) has been intensely investigated due to its potent cardiovascular effects and strong association with the pathophysiological worsening of cardiac function in congestive heart failure (7,13,16,29,35). ET-1 is a 21 amino acid peptide predominantly synthesized and secreted by endothelial cells. The effects of ET-1 are dictated by binding to one of two G protein-linked receptor subtypes A or B (ET A or ET B ) (16). In th...

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Section: Mmp Activation Postfistulamentioning

confidence: 46%

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Murray

Gardner²,

Brower³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…32 MMPs have been divided into subgroups on the basis of substrate specificity and domain structure. 33 MMP2 and MMP9 are of particular interest because they break down collagen, elastin, and basement membrane components. They share a common domain structure that includes type II fibronectin-like domains, differentiating them from other MMPs.…”

Section: Discussionmentioning

confidence: 99%

Near-Infrared Fluorescent Imaging of Matrix Metalloproteinase Activity After Myocardial Infarction

et al. 2005

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Background-We used a molecular probe activated by protease cleavage to image expression of matrix metalloproteinases (MMPs) in the heart after myocardial infarction. Methods and Results-We synthesized and characterized a near-infrared fluorescent (NIRF) probe that is activated by proteolytic cleavage by MMP2 and MMP9. The NIRF probe was injected into mice at various time points up to 4 weeks after myocardial infarction induced by ligation of the left anterior descending coronary artery. NIRF imaging of MMP activity increased in the infarct region, with maximal expression at 1 to 2 weeks, persisting to 4 weeks. Zymography and real-time polymerase chain reaction analysis showed that MMP9 expression is increased at 2 to 4 days, and MMP2 expression is increased at 1 to 2 weeks. Dual-label confocal microscopy showed colocalization of NIRF imaging with neutrophils on day 2, and flow cytometric analysis confirmed that NIRF signal is associated with leukocytes in the infarct zone. Conclusions-This study demonstrates that the activity of MMPs in the myocardium may be imaged by use of specific activity-dependent molecular probes. (Circulation. 2005;111:1800-1805.)

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“…Numerous studies have implicated a direct contribution of MMPs in the pathophysiological dilatation that occurs in the failing heart (29,49). A potential connection between ET-1 and MMP induction in pathological disease states has been observed from investigations of tumor cell invasion, cancerous growth, arthritis, and vascular remodeling (1, 2, 5, 45, 46).…”

Section: Metalloproteinase Activation and Collagen Degradation Postfimentioning

confidence: 99%

ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

Murray¹,

McMillan²,

Brower³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Murray DB, McMillan R, Brower GL, Janicki JS. ETA selective receptor antagonism prevents ventricular remodeling in volume-overloaded rats. Am J Physiol Heart Circ Physiol 297: H109 -H116, 2009. First published May 8, 2009 doi:10.1152/ajpheart.00968.2008.-The objective of this study was to investigate the ability of selective endothelin receptor subtype A (ET A) endothelin receptor antagonism (ETA) to prevent the acute myocardial remodeling process secondary to volume overload. Left ventricular tissue from sham-operated (Sham) and untreated (Fist), and TBC-3214 (Fist ϩ ETA, 25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 )-treated fistula animals was analyzed for mast cell density, matrix metalloproteinase (MMP) activity, and extracellular collagen volume fraction (CVF) 1 and 5 days following the initiation of volume overload. Compared with Fist, ETA treatment prevented the increase in left ventricular mast cell density at 1 day and 5 days. Additionally, at 1 day postfistula, a substantial decrease in MMP-2 activity below Sham levels was observed following endothelin receptor antagonism (1.7 Ϯ 0.7 vs. 0.3 Ϯ 0.3 vs. 0.9 Ϯ 0.2 arbitrary activity units, Fist vs. Fist ϩ ETA vs. Sham, P Յ 0.05). This same effect was also seen at 5 days postfistula (1.9 Ϯ 0.3 vs. 0.5 Ϯ 0.1 arbitrary activity units, Fist vs. Fist ϩ ETA, P Յ 0.05). The marked decrease in myocardial CVF seen in Fist hearts (0.7 Ϯ 0.1 vs. 1.6 Ϯ 0.1% myocardial area, Fist vs. Sham, P Յ 0.05) was prevented by ETA (1.7 Ϯ 0.1% Fist ϩ ETA, P Ͻ 0.05 vs. Fist). This preservation of the collagen matrix was also present on day 5 in the TBC-treated group vs. the Fist group (1.0 Ϯ 0.1 vs. 1.4 Ϯ 0.1%, Fist vs. Fist ϩ ETA, P Յ 0.01). Furthermore, an 8-wk preventative treatment with ETA significantly attenuated the increase in left ventricular end systolic and diastolic volumes compared with untreated fistula hearts. In conclusion, the novel findings of this study indicate that the activation of cardiac mast cells and subsequent MMP activation/collagen degradation during the acute stages of volume overload are prevented by blockade of the ET A receptor subtype. Furthermore, by preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits.endothelin-1; mast cell; matrix metalloproteinase; TBC-3214 ENDOTHELIN (ET)-1 is a potent neurohormone produced throughout the cardiovascular system, and the observation that plasma ET-1 is elevated in patients with heart failure is suggestive of a role in the pathophysiology of heart failure (16,19,34,40,47). The cardiovascular effects of ET-1 (a 21-amino-acid peptide) are dictated by binding to one of two G protein-linked receptor subtypes [endothelin receptor subtypes A (ET A ) or B (ET B )] (23). In the heart and vasculature, binding and activation of ET A is known to mediate powerful vasoconstrictor and pressor affects, in addition to chronotropic and ionotropic effects (12,25). The ET B receptor subtype is responsible for systemic clearance of circulating ...

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Extracellular degradative pathways in myocardial remodeling and progression to heart failure

Cited by 46 publications

References 25 publications

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Near-Infrared Fluorescent Imaging of Matrix Metalloproteinase Activity After Myocardial Infarction

ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

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Extracellular degradative pathways in myocardial remodeling and progression to heart failure

Cited by 46 publications

References 25 publications

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Near-Infrared Fluorescent Imaging of Matrix Metalloproteinase Activity After Myocardial Infarction

ETAselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

Contact Info

Product

Resources

About

ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats