title: Antioxidant treatment protects against matrix metalloproteinase activation and cardiomyocyte injury during acute pulmonary thromboembolism.
abstract: Increased reactive oxygen species (ROS) promote matrix metalloproteinase (MMP) activities and may underlie cardiomyocyte injury and the degradation of cardiac troponin I (cTI) during acute pulmonary thromboembolism (APT). We examined whether pretreatment or therapy with tempol (a ROS scavenger) prevents MMP activation and cardiomyocyte injury of APT. Anesthetized sheep received tempol infusion (1.0 mg kg(-1) min(-1), i.v.) or saline starting 30 min before or 30 min after APT (autologous blood clots). Control animals received saline. Hemodynamic measurements were performed. MMPs were studied in the right ventricle (RV) by gelatin zymography, fluorimetric activity assay, and in situ zymography. The ROS levels were determined in the RV and cTI were measured in serum samples. APT increased the pulmonary arterial pressure and pulmonary vascular resistance by 146 and 164%, respectively. Pretreatment or therapy with tempol attenuated these increases. While APT increased RV + dP/dt (max), tempol infusions had no effects. APT increased RV MMP-9 (but not MMP-2) levels. In line with these findings, APT increased RV MMP activities, and this finding was confirmed by in situ zymography. APT increased the RV ROS levels and tempol infusion, before or after APT, and blunted APT-induced increases in MMP-9 levels, MMP activities, in situ MMP activities, and ROS levels in the RV. cTI concentrations increased after APT, and tempol attenuated these increases. RV oxidative stress after APT increases the RV MMP activities, leading to the degradation of sarcomeric proteins, including cTI. Antioxidant treatment may prevent MMP activation and protect against cardiomyocyte injury after APT.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto 14049-900, São Paulo, Brazil.
authors.forename: Ozelia
authors.initials: O
authors.lastname: Sousa-Santos
authors.forename: Evandro M
authors.initials: EM
authors.lastname: Neto-Neves
authors.forename: Karina C
authors.initials: KC
authors.lastname: Ferraz
authors.forename: Carla S
authors.initials: CS
authors.lastname: Ceron
authors.forename: Elen
authors.initials: E
authors.lastname: Rizzi
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Gerlach
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002633:Chemotaxis; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012756:Sheep; D013113:Spin Labels; D019210:Troponin I / Q000378:metabolism
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D019210:Troponin I; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C001803:tempol