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1.
Atherosclerosis ; 198(2): 320-31, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18054360

ABSTRACT

Altered activity of matrix metalloproteinases (MMPs) is implicated in the vascular remodeling of hypertension. We examined whether increased MMP-2 expression/activity plays a role in the vascular remodeling and dysfunction found in the two-kidney, one-clip (2K-1C) hypertension. Sham operated or 2K-1C hypertension rats were treated with doxycycline 30mg/(kgday) (or vehicle). Systolic blood pressure was monitored weekly. After 8 weeks of treatment, aortic rings were isolated to assess endothelium-dependent and independent relaxations. Quantitative morphometry of structural changes, collagen, and elastin contents in the aortic wall were studied in hematoxylin/eosin, Sirius Red, and Orceine stained aortic sections, respectively. Aortic MMP-2 levels were determined by gelatin zymography and aortic MMP-2 proteolytic activity was measured using DQ gelatin as the substrate after MMP-2 was captured by a specific antibody and immobilized on a microplate. Aortic MMP-2/tissue inhibitor of metalloproteinases (TIMP)-2 mRNA levels were determined by real time RT-PCR. Doxycycline attenuated 2K-1C hypertension (215+/-8mmHg versus 167+/-13mmHg in 2K-1C rats and 2K-1C+doxy rats, respectively; P<0.01) and prevented the 35% reduction in endothelium-dependent vasorelaxation found in 2K-1C rats. Doxycycline prevented the increases in media thickness, and was associated with lower media/lumen and cross-sectional areas (all P<0.01). Doxycycline also prevented excessive collagen and elastin deposition in the vascular wall. Increased MMP-2 and Pro-MMP-2 levels and MMP-2 activity were found in the aortas of 2K-1C rats (all P<0.05). A 21-fold increase (P<0.001) in the ratio of MMP-2/TIMP-2 mRNA expression was found in the 2K-1C group, whereas this ratio remained unaltered in 2K-1C+doxy rats. Our results suggest that MMP-2 plays a role in 2K-1C hypertension and its structural and functional vascular changes, which were attenuated by doxycycline.


Subject(s)
Aorta, Thoracic/physiopathology , Doxycycline/pharmacology , Enzyme Precursors/antagonists & inhibitors , Gelatinases/antagonists & inhibitors , Hypertension, Renal/physiopathology , Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/pharmacology , Animals , Aorta, Thoracic/enzymology , Enzyme Precursors/genetics , Enzyme Precursors/metabolism , Gelatinases/genetics , Gelatinases/metabolism , Hypertension, Renal/enzymology , Male , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Metalloendopeptidases/genetics , Metalloendopeptidases/metabolism , RNA, Messenger/metabolism , Rats , Rats, Wistar , Tissue Inhibitor of Metalloproteinase-2/genetics , Tissue Inhibitor of Metalloproteinase-2/metabolism , Vasodilation
2.
Int J Cardiol ; 114(1): 22-7, 2007 Jan 02.
Article in English | MEDLINE | ID: mdl-16650492

ABSTRACT

BACKGROUND: Matrix metalloproteinases (MMPs) modulate vascular contractility and may affect acute pulmonary embolism (APE)-induced pulmonary hypertension. We examined the effects of the administration of doxycycline (a MMP inhibitor) following APE in anesthetized dogs. METHODS: Sham operated dogs (N=5) received only saline. APE was induced by intravenous injections of microspheres in amounts to increase mean pulmonary artery pressure (MPAP) by 20 mm Hg, and embolized dogs received saline (Emb group, N=8), or doxycycline (10 mg/kg, i.v.) 5 or 30 min of APE (Emb+Doxy 5 and Emb+Doxy 30 groups, N=9 and 8, respectively). Hemodynamic evaluation was performed at baseline and 5-120 after APE. Gelatin zymography of MMP-2 and MMP-9 from plasma samples was performed. RESULTS: No significant hemodynamic changes were found in Sham animals. Embolization increased MPAP by 218+/-16% and the pulmonary vascular resistance index (PVRI) by 289+/-42% in Emb group (both P<0.05). Doxycyline increased the cardiac index by 24+/-5% and reduced PVRI by 23+/-4% 120 min of APE in Doxy 30+Emb group. In addition, doxycyline reduced MPAP and PVRI 30 min after APE with maximum effects seen 120 min after APE (25+/-4% decrease in MPAP and 33+/-6% decrease in PVRI; both P<0.05) in Doxy+5 group. Plasma pro-MMP-9 and MMP-9 levels increased only in Emb group and MMP-2 remained unaltered. CONCLUSIONS: Our study shows that doxycycline attenuates APE-induced pulmonary hypertension, and indicates that MMP-9 has a role in APE-induced pulmonary hypertension. MMP-9 may be a pharmacological target in APE.


Subject(s)
Matrix Metalloproteinase 9/physiology , Pulmonary Embolism/enzymology , Pulmonary Embolism/physiopathology , Acute Disease , Animals , Dogs , Doxycycline/pharmacology , Female , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/physiopathology , Male , Matrix Metalloproteinase 2/physiology , Matrix Metalloproteinase Inhibitors , Pulmonary Embolism/complications
3.
Crit Care Med ; 35(1): 239-45, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17133179

ABSTRACT

OBJECTIVE: Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of acute pulmonary embolism (APE)-induced pulmonary hypertension. Here, we evaluate the effects of atorvastatin pretreatment on APE-induced pulmonary hypertension, 24-hr mortality rate, and changes in plasma and lung MMP-2 and MMP-9 activities. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Rats received atorvastatin (30 mg/kg/day orally) or tap water for 2 wks. In study 1, we examined whether atorvastatin affected APE-induced pulmonary hypertension by using a rat isolated lung perfusion model of APE. In study 2, we examined whether atorvastatin affects the survival rate after APE, which was induced by rapid intravenous injection of 14 mg/kg of a suspension of microspheres (or saline) into the tail vein. MEASUREMENTS AND MAIN RESULTS: Plasma nitrite/nitrate concentrations were measured by chemiluminescence. Pretreatment with atorvastatin was associated with 49% higher nitrite/nitrate levels compared with controls (p < .05). In study 1, whereas APE increased mean pulmonary artery pressure (MPAP) by 13.0 +/- 1.6 mm Hg in perfused lungs isolated from rats pretreated with water, pretreatment with atorvastatin attenuated by 27% the increases in MPAP after APE. In study 2, pretreatment with atorvastatin was associated with a significant increase in 24-hr survival rate after APE, which was 48% in embolized rats pretreated with water and 64% in rats pretreated with atorvastatin (p < .05). Gelatin zymography of lung and plasma MMP-2 and MMP-9 was performed. Lungs and plasma from embolized rats showed higher levels of both pro- and activated forms of MMP-9 compared with those from nonembolized animals (all p < .05). However, pretreatment with atorvastatin attenuated by 32% the increases in lung-activated MMP-9 levels after APE (p < .05). CONCLUSIONS: These results suggest that pretreatment with atorvastatin attenuates APE-induced pulmonary hypertension and increases 24-hr survival rate by mechanisms that result in attenuated increases in lung activated MMP-9 after APE.


Subject(s)
Disease Models, Animal , Heptanoic Acids/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/prevention & control , Matrix Metalloproteinase 9 , Pyrroles/therapeutic use , Acute Disease , Analysis of Variance , Animals , Atorvastatin , Drug Evaluation, Preclinical , Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/mortality , Injections, Intravenous , Luminescence , Lung/chemistry , Male , Matrix Metalloproteinase 2/analysis , Matrix Metalloproteinase 2/drug effects , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/analysis , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/metabolism , Microspheres , Nitrates/blood , Nitrites/blood , Proportional Hazards Models , Pulmonary Embolism/complications , Pulmonary Wedge Pressure/drug effects , Pyrroles/pharmacology , Random Allocation , Rats , Rats, Wistar , Survival Rate
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