Matrix Metalloproteinase-2 Contributes to Ischemia-Reperfusion Injury in the Heart

Cheung, Po–Yin; Sawicki, Grzegorz; Woźniak, Mieczysław; Wang, Wenjie; Radomski, Marek W.; Schulz, Richard

doi:10.1161/01.cir.101.15.1833

Cited by 404 publications

(401 citation statements)

References 27 publications

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“…However, these increases were not paralleled by increased LV and plasma MMP-2 levels measured by gel zymography. Although we do not have a precise explanation for these findings, increased activation of cardiac MMP-2 activity has been found in association with depletion and lower cardiac MMP-2 levels during ischaemia-reperfusion experiments [36]. Further studies are necessary to determine the kinetics of MMP-2.…”

Section: Discussionmentioning

confidence: 75%

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

Ferraz

Sousa-Santos

Neto-Neves

et al. 2012

Basic Clin Pharma Tox

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Growing evidence supports the involvement of matrix metalloproteinases (MMPs) in the pathogenesis of many cardiovascular diseases. Particularly, imbalanced MMP-2 activity apparently plays a critical role in cardiovascular remodelling. While some studies have suggested that MMP-2 may affect the vascular tone and impair b-adrenoreceptor function, no previous study has examined the acute haemodynamic effects of MMP-2. We examined the effects of recombinant human MMP-2 (rhMMP-2) administered intravenously to anaesthetized lambs at baseline conditions and during b 1 -adrenergic cardiac stimulation with dobutamine. We used 26 anaesthetized male lambs in two study protocols. First, rhMMP-2 (220 ng/kg/min. over 60 min.) or vehicle was infused in the lambs, and no significant haemodynamic changes were found. Therefore, we infused dobutamine at 5 lg/kg/ min. i.v. (or saline) over 180 min. in lambs that had received the same rhMMP-2 infusion preceded by doxycycline i.v. at 10 mg/kg (or saline). Plasma and cardiac MMP-2 levels were assessed by gelatin zymography, and gelatinolytic activity was assessed by spectrofluorimetry. Dobutamine decreased systemic vascular resistance index, and this effect was attenuated by rhMMP-2 infusion. Moreover, dobutamine increased the cardiac index and left ventricular dP/dt max , and these effects were attenuated by rhMMP-2. The previous administration of doxycycline blunted rhMMP-2-induced changes in dobutamine responses. While the infusion of rhMMP-2 did not increase plasma and cardiac MMP-2 levels, it increased cardiac gelatinolytic activity, and doxycycline blunted this effect. Our findings show that rhMMP-2 exerts no major haemodynamic effects in lambs. However, rhMMP-2 impairs the responses elicited by activation of b-adrenoreceptors.Growing evidence supports the involvement of a group of enzymes named matrix metalloproteinases (MMPs) in the pathogenesis of many disease conditions, including diseases affecting the cardiovascular system [1][2][3][4]. Particular attention has been paid to MMP-2 because imbalanced MMP-2 activity apparently plays a critical role in cardiovascular remodelling [5][6][7] and in other alterations of the cardiovascular system [8][9][10]. However, recent studies are clearly showing that MMP-2 may have many other targets unrelated to the extracellular matrix, including intracellular substrates [11,12] and other mediators possibly affecting the vascular tone such as bigendothelin-1[13], calcitonin gene-related peptide [14] and adrenomedullin [15]. Importantly, activated MMP-2 has been shown to impair cardiac function possibly as a result of its activity targeting sarcomeric and cytoskeletal proteins such as troponin I, myosin light chain-1, a-actinin and titin [16][17][18][19][20].Recent studies indicate that MMPs, including MMP-2, are involved in proteolytic cleavage of b 1 -and b 2 -adrenoreceptors [21]. Rodrigues et al. [22] demonstrated that the labelling density of the extracellular domain of b 2 -adrenergic receptor in aortic endothelial cells fro...

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Section: Discussionmentioning

confidence: 75%

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

Ferraz

Sousa-Santos

Neto-Neves

et al. 2012

Basic Clin Pharma Tox

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“…PCR was performed with a PCR-kit in the presence of oligo-primers for MMP-2 (Assay ID: Mm00439498 m1), MMP-9 (Assay ID: Mm00600163 m1), TIMP1 (Assay ID: Mm00441818 m1), TIMP2 (Assay ID: Mm00441825 m1), BNP (Assay ID: Mm1255770-g1), TGFbeta (Assay ID: Mm01178820 m1), collagen I (Assay ID: Mm01302043-g1), Myh7 (Assay ID: Mm01319006-g1), NPPA (Assay ID: Mm01255747-g1) and 18s rRNA as a control. 20,21) Quantitative data were calculated using the comparative CT (∆∆CT) method and the mRNA expression was normalized by native samples. In-gel zymography: In-gel zymography was performed using gelatin in an SDS gel as the substrate.…”

Section: )mentioning

confidence: 99%

Periodontal Pathogen Aggregatibacter actinomycetemcomitans Deteriorates Pressure Overload-Induced Myocardial Hypertrophy in Mice

et al. 2012

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SummaryAlthough a relationship between periodontitis and myocardial hypertrophy has been reported, the precise mechanism has not been clarified. The purpose of this study was to investigate the association between periodontal infection and myocardial hypertrophy. Transverse aortic constriction (TAC) was performed. Mice were injected with Aggregatibacter actinomycetemcomitans (A.a.) (0.1 mL of 10 8 CFU/mL) in the infected group and PBS in the control group. Echocardiography, histopathology, and immunohistochemistry were performed. Echocardiography indicated that left ventricular fractional shortening had decreased in the infected group compared to the control group on day 28. Heart to body weight ratio increased in the infected group compared to the control group. Histopathologically, A.a.-infected mice showed markedly enhanced cardiac hypertrophy, fibrosis and arteriosclerosis 4 weeks after TAC operation. Immunohistochemistry revealed that expression of MMP-2 in the interstitial tissue was enhanced in the infected group. These results suggested that the periodontal pathogen caused a deterioration of pressure overload-induced myocardial hypertrophy through MMP activation. (Int Heart J 2012; 53: 324-330)

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“…MMP contributes importantly to the development of various pathophysiological conditions, including dilated cardiomyopathy, congestive heart failure, and reperfusion injury. [25][26][27][28] Oxidative stress causes tissue injury through activation of the precursors of MMPs (proMMPs). The activation of proMMPs is triggered by peroxynitrite generation via an extensive S-glutathiolation reaction.…”

Section: Effects Of Fp 15 On Myocardial Damage Produced By Transient mentioning

confidence: 99%

Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-Induced Cardiac Dysfunction

et al. 2003

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Background-Increased oxidative stress and dysregulation of nitric oxide have been implicated in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide in various forms of cardiac injury. Using a novel metalloporphyrinic peroxynitrite decomposition catalyst, FP15, and nitric oxide synthase inhibitors or knockout mice, we now delineate the pathogenetic role of peroxynitrite in rodent models of DOX-induced cardiac dysfunction. Methods and Results-Mice received a single injection of DOX (25 mg/kg IP). Five days after DOX administration, left ventricular performance was significantly depressed, and high mortality was noted. Treatment with FP15 and an inducible nitric oxide synthase inhibitor, aminoguanidine, reduced DOX-induced mortality and improved cardiac function. Genetic deletion of the inducible nitric oxide synthase gene was also accompanied by better preservation of cardiac performance. In contrast, inhibition of the endothelial isoform of nitric oxide synthase with N-nitro-L-arginine methyl ester increased DOX-induced mortality. FP15 reduced the DOX-induced increase in serum LDH and creatine kinase activities. Furthermore, FP15 prevented the DOX-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart but not NAD(P)H-driven superoxide generation. Peroxynitrite neutralization did not interfere with the antitumor effect of DOX. FP15 also decreased ischemic injury in rats and improved cardiac function and survival of mice in a chronic model of DOX-induced cardiotoxicity. Conclusions-Thus

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Matrix Metalloproteinase-2 Contributes to Ischemia-Reperfusion Injury in the Heart

Abstract: These results show that acute release of MMP-2 during reperfusion after ischemia contributes to cardiac mechanical dysfunction. The inhibition of MMPs may be a novel pharmacological strategy for the treatment of ischemia-reperfusion injury.

Cited by 404 publications

References 27 publications

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

Periodontal Pathogen Aggregatibacter actinomycetemcomitans Deteriorates Pressure Overload-Induced Myocardial Hypertrophy in Mice

Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-Induced Cardiac Dysfunction

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