Matrix Metalloproteinases as Drug Targets in Acute Pulmonary Embolism
Department of Pharmacology, Faculty of Medicine University of Sao Paulo Av. Bandeirantes, 3900 14049-900 Ribeirao Preto, SP, Brazil. Current drug targets
(Impact Factor: 3.02).
01/2013; 14(3). DOI: 10.2174/1389450111314030006
Acute pulmonary embolism is a critical condition associated with increased mortality. Lung embolization causes acute pulmonary hypertension and right ventricle afterload. Global heart ischemia supervenes and may lead to severe shock and death. In this article, we reviewed current literature supporting the idea that abnormal matrix metalloproteinase (MMP) activity contributes to acute pulmonary embolism-induced hemodynamic changes. While low MMP levels are usually found in normal lung tissues, it is well known that inflammation and lung injury increase MMP expression and activity. This is probably due to recruitment and migration of inflammatory cells from the circulation to lung tissues. In addition, recent studies have shown increased MMP levels and activity in the right ventricle from animals with acute pulmonary embolism. Such increases in proteolytic activity were associated with increased cardiac troponin I in serum, suggesting a possible role for MMPs in cardiomyocyte injury during acute pulmonary embolism. These alterations have justified the use of doxycycline as an MMP inhibitor in acute pulmonary embolism. We review current evidence indicating that MMPs are targets in this critical condition. MMP inhibition apparently exerts antihypertensive effects and protects against cardiomyocyte injury caused by acute pulmonary embolism.
Available from: Paras Kumar Mishra
- "Although significant role of MMP-2 in remodeling has been extensively reported, recent report suggests that the infusion of recombinant human MMP-2 in lambs did not alter any hemodynamic parameters but for the impairment of beta adrenoceptor activation response . The involvement of MMPs in left ventricular pathology has been extensively reported  however, a recent study in acute pulmonary thromboembolism (APT) showed a similar role in right ventricular remodeling . In APT, ROS production was associated with MMP activation and treatment with non-specific MMP inhibitors or antioxidants were found to mitigate MMP induced remodeling  . "
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ABSTRACT: Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is attributed to its matrix that maintains structural and functional integrity and provides ambient micro-environment required for mechanical, cellular and molecular activities in the heart. Cardiac matrix dictates the endothelium-myocyte (E-M) coupling and contractility of cardiomyocytes. The matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) regulate matrix degradation that determines cardiac fibrosis and myocardial performance. We have shown that MMP-9 regulates differential expression of micro RNAs (miRNAs), calcium cycling and contractility of cardiomyocytes. The differential expression of miRNAs is associated with angiogenesis, hypertrophy and fibrosis in the heart. MMP-9, which is involved in the degradation of cardiac matrix and induction of fibrosis, is also implicated in inhibition of survival and differentiation of cardiac stem cells (CSC). Cardiac matrix is distinct because it renders mechanical properties and provides a framework essential for differentiation of cardiac progenitor cells (CPC) into specific lineage. Cardiac matrix regulates myocyte contractility by E-M coupling and calcium transients and also directs miRNAs required for precise regulation of continuous and synchronized beating of cardiomyocytes that is indispensible for survival. Alteration in the matrix homeostasis due to induction of MMPs, altered expression of specific miRNAs or impaired signaling for contractility of cardiomyocytes leads to catastrophic effects. This review describes the mechanisms by which cardiac matrix regulates myocardial performance and suggests future directions for the development of treatment strategies in cardiovascular diseases.
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ABSTRACT: Acute pulmonary thromboembolism (APT) is a critical condition associated with acute pulmonary hypertension. Recent studies suggest that oxidative stress and hemolysis contribute to APT-induced pulmonary hypertension, possibly as a result of increased nitric oxide (NO) consumption. We hypothesized that the antioxidant tempol could attenuate APT-induced hemolysis, and therefore attenuate APT-induced increases in plasma NO consumption.
APT was induced in anesthetized sheep with autologous blood clots. The hemodynamic effects of tempol infused at 1.0mg/kg/min 30min after APT were determined. Hemodynamic measurements were carried out every 15min. To assess oxidative stress, serum 8-isoprostanes levels were measured by ELISA. Plasma cell-free hemoglobin concentrations and NO consumption by plasma samples were determined. An in vitro oxidative AAPH-induced hemolysis assay was used to further validate the in vivo effects of tempol.
APT caused pulmonary hypertension, and increased pulmonary vascular resistance in proportion with the increases in 8-isoprostanes, plasma cell-free hemoglobin concentrations, and NO consumption by plasma (all P<0.05). Tempol attenuated the hemodynamic alterations by approximately 15-20% and blunted APT-induced increases in 8-isoprostanes, in cell-free hemoglobin concentrations, and the increases in NO consumption by plasma (P<0.05). Tempol dose-dependently attenuated AAPH-induced in vitro hemolysis (P<0.05).
Our findings are consistent with the idea that antioxidant properties of tempol decrease APT-induced hemolysis and nitric oxide consumption, thus attenuating APT-induced pulmonary hypertension.
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