Effects of Matrix Metalloproteinase Inhibition on Ventricular Remodeling Due to Volume Overload

Chancey, Amanda L.; Brower, Gregory L.; Peterson, Janet T.; Janicki, Joseph S.

doi:10.1161/01.cir.0000014686.73212.da

Cited by 129 publications

(121 citation statements)

References 38 publications

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“…Mast cell-mediated MMP activation, leading to degradation of the extracellular matrix and ventricular dilatation, are well-documented features in this model of heart failure (3,6,8,9,20). The stimulus initiating this mast cell-mediated remodeling is unknown; however, we recently demonstrated that ET-1 is capable of causing cardiac mast cell degranulation and the subsequent activation of MMPs ex vivo (31).…”

Section: Discussionmentioning

confidence: 82%

“…Previous studies from our laboratory using the aortocaval (AV) fistula model of volume overload established a causal role for cardiac mast cells in the activation of matrix metalloproteinases (MMPs) (3,8,22,31). The role of MMPs in mediating the degradation of the extracellular matrix leading to ventricular dilatation has been well documented (3,6,9,20,38). However, the potential for ET-1 to directly impact myocardial remodeling was recently established by our study, demonstrating that ET-1 causes degranulation of resident cardiac mast cells (31).…”

mentioning

confidence: 99%

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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: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

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

Self Cite

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“…In the setting of pure volume overload through the creation of arteriovenous fistula, Chancey et al (19) have confirmed that the administration of an MMP inhibitor can effectively decrease cardiac dilation, reduce wall stress and left ventricular hypertrophy, and preserve ventricular function.…”

Section: Mmps In Cardiovascular Diseasementioning

confidence: 98%

Matrix metalloproteinases in cardiovascular disease

Liu¹,

Sun²,

Sader³

2006

Canadian Journal of Cardiology

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“…In contrast to the marked accentuation in collagen deposition triggered by a pressure load, volume overload is associated with a reduction in interstitial collagen content due to increased MMP expression (113)(114)(115) and augmented autophagic degradation of procollagen in cardiac fibroblasts (116). Pharmacologic inhibition studies suggested that MMP activation is directly implicated in dilative remodeling of the volume-overloaded ventricle (117), but the mechanisms responsible for the distinct cell biological changes and matrix alterations in volume overload remain poorly understood. Bradykinin receptor signaling has been implicated in matrix loss associated with volume overload (118), but the links between specific mechanical stimuli and myocardial cell activation are understudied.…”

Section: Ecm In Cardiac Pressure and Volume Overloadmentioning

confidence: 99%