Cardiac transgenic matrix metalloproteinase-2 expression directly induces impaired contractility

Wang, Guanying; Bergman, Marina; Nguyen, Anita; Turcato, Sally; Swigart, Philip M.; Rodrigo, Manoj C.; Simpson, Paul C.; Karliner, Joel S.; Lovett, David H.; Baker, Anthony J.

doi:10.1016/j.cardiores.2005.08.023

Cited by 81 publications

(84 citation statements)

References 35 publications

(36 reference statements)

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“…Although we have not determined molecular mechanisms in the present study, our findings are consistent with a recent report showing that GM6001 (a non-specific MMP inhibitor) prevented the cleavage of the N-terminus of the b 1 -adrenergic receptor [24]. Giving further support to our findings, increased MMP-2 expression impaired contraction and reduced the responses to inotropic stimulation in transgenic mice overexpressing MMP-2 [37,38]. Together, these findings strongly indicate that abnormal MMP-2 activity can directly impair LV function.…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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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“…Thus these mice exhibited hemodynamic compensation in the basal state, although, as noted above, the response of isolated right ventricular trabeculae from these mice to inotropic stimulation was impaired (61). However, by 12 mo of age an increased mortality in the MMP-2 transgenic mice was evident, as were manifestations of overt congestive heart failure, including reduced activity, ascites, and cyanosis.…”

Section: Discussionmentioning

confidence: 71%

“…Taken together, the ultrastructural changes in the cardiac MMP-2 transgenic mice are most consistent with a primary cardiomyopathy phenotype. Support for this conclusion is provided by our recent observation (61) that isolated right ventricular trabeculae from MMP-2 cardiac transgenics exhibited impaired contractile force and diminished responses to inotropic stimulation. The contractile force of skinned trabeculae from MMP-2 cardiac transgenics was also diminished, consistent with a primary myofilament contraction defect.…”

Section: Discussionmentioning

confidence: 87%

Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction

Bergman¹,

Teerlink²,

Mahimkar³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

168

133

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DH. Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction. Am J Physiol Heart Circ Physiol 292: H1847-H1860, 2007. First published December 8, 2006; doi:10.1152/ajpheart.00434.2006.-Although enhanced cardiac matrix metalloproteinase (MMP)-2 synthesis has been associated with ventricular remodeling and failure, whether MMP-2 expression is a direct mediator of this process is unknown. We generated transgenic mice expressing active MMP-2 driven by the ␣-myosin heavy chain promoter. At 4 mo MMP-2 transgenic hearts demonstrated expression of the MMP-2 transgene, myocyte hypertrophy, breakdown of Z-band registration, lysis of myofilaments, disruption of sarcomere and mitochondrial architecture, and cardiac fibroblast proliferation. Hearts from 8-mo-old transgenic mice displayed extensive myocyte disorganization and dropout with replacement fibrosis and perivascular fibrosis. Older transgenic mice also exhibited a massive increase in cardiac MMP-2 expression, representing recruitment of endogenous MMP-2 synthesis, with associated expression of MMP-9 and membrane type 1 MMP. Increases in diastolic [control (C) 33 Ϯ 3 vs. MMP 51 Ϯ 12 l; P ϭ 0.003] and systolic (C 7 Ϯ 2 vs. MMP 28 Ϯ 14 l; P ϭ 0.003) left ventricular (LV) volumes and relatively preserved stroke volume (C 26 Ϯ 4 vs. MMP 23 Ϯ 3 l; P ϭ 0.16) resulted in markedly decreased LV ejection fraction (C 78 Ϯ 7% vs. MMP 48 Ϯ 16%; P ϭ 0.0006). Markedly impaired systolic function in the MMP transgenic mice was demonstrated in the reduced preload-adjusted maximal power (C 240 Ϯ 84 vs. MMP 78 Ϯ 49 mW/l 2 ; P ϭ 0.0003) and decreased end-systolic pressure-volume relation (C 7.5 Ϯ 1.5 vs. MMP 4.7 Ϯ 2.0; P ϭ 0.016). Expression of active MMP-2 is sufficient to induce severe ventricular remodeling and systolic dysfunction in the absence of superimposed injury. heart failure; fibrosis; mitochondria; sarcomere THE PAST DECADE HAS WITNESSED an increasing interest in the interactions of cardiomyocytes with the extracellular matrix, particularly with regard to the development of cardiac failure and fibrosis. Modulation of the cardiac extracellular matrix by various members of the large matrix metalloproteinase (MMP) gene family has provided important mechanistic insights into the evolution of left ventricular failure in the setting of both ischemic and nonischemic disease (10,11,20,29,49,51). The MMP gene family includes Ͼ20 discrete members, including the interstitial collagenases (e.g., MMP-1 and -13), the gelatinases (MMP-2, -9), and membrane-associated enzymes, including membrane type 1(MT1)-MMP (60). MMP-2 has the been the focus of considerable interest, as previous studies in animal models of heart failure, including the salt-sensitive hypertensive rat (19, 43), mitral regurgitation in the dog (52), and experimental myocardial infarction in the rat (41), have all shown excessive activation of MMP-2 as heart failure progressed. Inhibition of MMP-2 activation with nonselective agents, including an angiotensin-...

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“…Our previous study 10 and a recent study by Matsumura et al 22 have demonstrated that the inhibition of MMP 2 activity improves the survival rate after acute MI by preventing cardiac rupture and delays after MI remodeling. A recent study by Wang et al 23 has shown that cardiac-specific, constitutively active MMP 2 expression leads to impaired contraction and diminished responses to inotropic stimulation, indicating that MMP 2 can directly impair cardiac function in the absence of superimposed injury. Broad-spectrum pharmacological inhibition of MMPs significantly attenuated myocardial remodeling associated with chronic volume overload 3 or hypertension.…”

Section: Role Of Mmp 2 In Po Hypertrophymentioning

confidence: 99%

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

et al. 2006

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Abstract-Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (nϭ10) and sibling wild-type (WT) mice (nϭ9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.

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Cardiac transgenic matrix metalloproteinase-2 expression directly induces impaired contractility

Abstract: Cardiac-specific, constitutively active MMP-2 expression leads to impaired contraction and diminished responses to inotropic stimulation. These findings indicate that MMP-2 can directly impair ventricular function in the absence of superimposed injury.

Cited by 81 publications

References 35 publications

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

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

Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

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