Antioxidant treatment protects against matrix metalloproteinase activation and cardiomyocyte injury during acute pulmonary thromboembolism

Sousa-Santos, Ozélia; Neto-Neves, Evandro M.; Ferraz, Karina Coutinho; Ceron, Carla S.; Rizzi, Élen; Gerlach, Raquel Fernanda; Tanus‐Santos, Jose E.

doi:10.1007/s00210-012-0748-9

Cited by 19 publications

(13 citation statements)

References 42 publications

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“…with a commercially available kit (Vidas Troponin I Ultra‐TNIU, Biomérieux, Durham, NC, USA) according to the manufacturer's instructions. The detection limit for this assay is 0.01 μg/l of cTnI .…”

Section: Methodsmentioning

confidence: 96%

Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism

Neto-Neves

Sousa-Santos

Ferraz

et al. 2013

J Cellular Molecular Medi

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Activated matrix metalloproteinases (MMPs) cause cardiomyocyte injury during acute pulmonary thromboembolism (APT). However, the functional consequences of this alteration are not known. We examined whether doxycycline (a MMP inhibitor) improves right ventricle function and the cardiac responses to dobutamine during APT. APT was induced with autologous blood clots (350 mg/kg) in anaesthetized male lambs pre-treated with doxycycline (Doxy, 10 mg/kg/day, intravenously) or saline. Non-embolized control lambs received doxycycline pre-treatment or saline. The responses to intravenous dobutamine (Dob, 1, 5, 10 μg/kg/min.) or saline infusions at 30 and 120 min. after APT induction were evaluated by echocardiography. APT increased mean pulmonary artery pressure and pulmonary vascular resistance index by ∼185%. Doxycycline partially prevented APT-induced pulmonary hypertension (P < 0.05). RV diameter increased in the APT group (from 10.7 ± 0.8 to 18.3 ± 1.6 mm, P < 0.05), but not in the Doxy+APT group (from 13.3 ± 0.9 to 14.4 ± 1.0 mm, P > 0.05). RV dysfunction on stress echocardiography was observed in embolized lambs (APT+Dob group) but not in embolized animals pre-treated with doxycycline (Doxy+APT+Dob). APT increased MMP-9 activity, oxidative stress and gelatinolytic activity in the RV. Although doxycycline had no effects on RV MMP-9 activity, it prevented the increases in RV oxidative stress and gelatinolytic activity (P < 0.05). APT increased serum cardiac troponin I concentrations (P < 0.05), doxycycline partially prevented this alteration (P < 0.05). We found evidence to support that doxycycline prevents RV dysfunction and improves the cardiac responses to dobutamine during APT.

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Section: Methodsmentioning

confidence: 96%

Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism

Neto-Neves

Sousa-Santos

Ferraz

et al. 2013

J Cellular Molecular Medi

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“…Gelatin zymography of MMP-2 from LV and plasma samples was performed as previously described [30][31][32]. Briefly, tissues were homogenized in extraction buffer containing 10 mM CaCl 2 , 50 mM Tris-HCl, pH 7.4, 1 mM 1,10-phenanthroline, 1 mM phenylmethylsulfonyl fluoride (PMSF), 1 mM N-ethyl maleimide (NEM).…”

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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“…In animal models, inhibitors of either MMPs [51] or cathepsins[52] successfully blocked the progression of cerebral aneurysms, highlighting the key role of these proteinases in aneurysm pathogenesis. The expression and activity of MMPs are at least in part ROS-dependant, with early remodeling requiring NADPH oxidase, while late remodeling being more dependent on ONOO• − generated by eNOS [19, 53–55]. Importantly, MMP-2 and −9, two major human proteinases that play a crucial role in aneurysm formation, [51] are regulated by free radicals including ONOO• − produced by VSMCs, endothelium and macrophages [19].…”

Section: Possible Pathways Of Oxidative Stress Induced Injury In Cerementioning

confidence: 99%

The Role of Oxidative Stress in Cerebral Aneurysm Formation and Rupture

Starke¹,

Chalouhi²,

Ali³

et al. 2013

CNR

122

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Oxidative stress is known to contribute to the progression of cerebrovascular disease. Additionally, oxidative stress may be increased by, but also augment inflammation, a key contributor to cerebral aneurysm development and rupture. Oxidative stress can induce important processes leading to cerebral aneurysm formation including direct endothelial injury as well as smooth muscle cell phenotypic switching to an inflammatory phenotype and ultimately apoptosis. Oxidative stress leads to recruitment and invasion of inflammatory cells through upregulation of chemotactic cytokines and adhesion molecules. Matrix metalloproteinases can be activated by free radicals leading to vessel wall remodeling and breakdown. Free radicals mediate lipid peroxidation leading to atherosclerosis and contribute to hemodynamic stress and hypertensive pathology, all integral elements of cerebral aneurysm development. Preliminary studies suggest that therapies targeted at oxidative stress may provide a future beneficial treatment for cerebral aneurysms, but further studies are indicated to define the role of free radicals in cerebral aneurysm formation and rupture. The goal of this review is to assess the role of oxidative stress in cerebral aneurysm pathogenesis.

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Antioxidant treatment protects against matrix metalloproteinase activation and cardiomyocyte injury during acute pulmonary thromboembolism

Cited by 19 publications

References 42 publications

Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism

Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism

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

The Role of Oxidative Stress in Cerebral Aneurysm Formation and Rupture

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