Metalloproteinase inhibition protects against cardiomyocyte injury during experimental acute pulmonary thromboembolism*

Neto-Neves, Evandro M.; Dias‐Junior, Carlos A.; Rizzi, Élen; Castro, Michele M.; Sônego, Fabiane; Gerlach, Raquel Fernanda; Tanus‐Santos, Jose E.

doi:10.1097/ccm.0b013e3181fa3dfe

Cited by 28 publications

(32 citation statements)

References 32 publications

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“…Increased cardiac MMP-2 expression in 2K1C hypertensive rats confers a more proteolytic profile that may account for increased collagen synthesis and breakdown. While increased proteolytic activity may contribute to degradation of myofilaments in acute cardiac conditions [35][36][37], chronic increases in this activity are associated with enhanced extracellular matrix deposition. This leads to hypertrophy likely because excessive MMP-2 activates pro-fibrotic intracellular pathways that increase collagen-I synthesis by cardiac fibroblasts [38].…”

Section: Discussionmentioning

confidence: 99%

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

Cau

Guimaraes

Rizzi

et al. 2015

Basic Clin Pharma Tox

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Imbalanced matrix metalloproteinase (MMP) activity is involved in hypertensive cardiac hypertrophy. Pharmacological inhibition of nuclear factor kappaB (NF-кB) with pyrrolidine dithiocarbamate (PDTC) can prevent MMP up-regulation. We suggested that treatment with PDTC could prevent 2-kidney, 1-clip (2K1C) hypertension-induced left ventricular remodelling. Sham-operated controls or 2K1C rats with hypertension received either vehicle or PDTC (100 mg/kg/day) by gavage for 8 weeks. Systolic blood pressure was monitored every week. Histological assessment of left ventricles was carried out with haematoxylin/eosin sections, and fibrosis was quantified in picrosirius red-stained sections. Oxidative stress was evaluated in heart samples with the dihydroethidium probe. Cardiac MMP activity was determined by in situ zymography, and cardiac MMP-2 was assessed by immunofluorescence. 2K1C surgery significantly increased systolic blood pressure in the 2K1C vehicle. PDTC exerted antihypertensive effects after 2 weeks of treatment. Histology revealed increased left ventricular and septum wall thickness associated with augmented myocyte diameter in hypertensive rats, which were reversed by treatment with PDTC. Hypertensive rats developed pronounced cardiac fibrosis with increased interstitial collagen area, increased cardiac reactive oxygen species levels, gelatinase activity and MMP-2 expression. PDTC treatment decreased these alterations. These findings show that PDTC modulates myocardial MMP-2 expression and ameliorates cardiac remodelling in renovascular hypertension. These results suggest that interfering with MMP expression at transcriptional level may be an interesting strategy in the therapy of organ damage associated with hypertension.It is well known that cardiac hypertrophy develops in response to many pathophysiological stimuli, particularly to pressure/volume overload and neurohormonal activation [1]. Although hypertension-associated cardiac remodelling is an initial adaptive process, sustained remodelling ultimately leads to progressive heart failure and death [1][2][3]. Common morphological features in hypertension-associated left ventricular remodelling include enlargement of cardiomyocytes and stimulated collagen turnover, resulting in net accumulation of interstitial collagen in cardiovascular tissues [3,4].Due to their fundamental role in extracellular matrix turnover and reorganization, matrix metalloproteinases (MMP), a so-called group of metalloenzymes, has been implicated as mediators of cardiac hypertrophy [5,6]. MMPs are proteases dependent on zinc and calcium and cleave several components of the extracellular matrix such as collagen, promoting the remodelling of tissue architecture and cell growth under both physiological and pathological conditions [7]. Additionally, MMP-2 degrades intracellular proteins such as troponin-I [8], myosin light chain [9], a-actinin [10] and titin [11], thus contributing to cardiac dysfunction. Transgenic mice with increased MMP-2 expression in cardiomyocytes deve...

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Section: Discussionmentioning

confidence: 99%

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

Cau

Guimaraes

Rizzi

et al. 2015

Basic Clin Pharma Tox

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“…The dose of rhMMP-2 was chosen with basis on the circulating MMP-2 levels commonly found in human beings [26]. The doses of dobutamine and doxycycline were chosen based on previous studies showing significant b-adrenergic stimulation of dobutamine in sheep [27] and beneficial haemodynamic effects of doxycycline with MMP inhibition [28,29], respectively.…”

Section: Methodsmentioning

confidence: 99%

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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“…We found that matrix metalloproteinase (MMP) activation, probably derived from infiltrating leucocytes or macrophages increase after acute PTE in proportion to the severity of the disease, thus leading to proportional increases in cardiac troponin I 2. Increased MMP levels after acute PTE may promote cardiomyocyte injury that is attenuated by MMP inhibitors or antioxidant drugs such as tempol, as previously shown experimentally 3. The important role of MMP activation may justify the use of MMP inhibitors such as doxycycline.…”

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confidence: 61%

Targeting cardiomyocyte injury in acute pulmonary thromboembolism

Tanus‐Santos

2012

Heart

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Metalloproteinase inhibition protects against cardiomyocyte injury during experimental acute pulmonary thromboembolism*

Cited by 28 publications

References 32 publications

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

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

Targeting cardiomyocyte injury in acute pulmonary thromboembolism

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