Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension.
Mounting evidence indicates that structural and functional vascular changes associated with two-kidney, one-clip (2K-1C) hypertension result, at least in part, from altered activity of matrix metalloproteinases (MMPs). Because MMPs are upregulated by increased formation of reactive oxygen species (ROS), we hypothesized that antioxidant approaches could attenuate the increases in MMP-2 expression/activity and the vascular dysfunction and remodeling associated with 2K-1C hypertension. Sham-operated or 2K-1C hypertensive rats were treated with tempol 18 mg/kg/day or apocyanin 25 mg/kg/day (or vehicle). Systolic blood pressure was monitored weekly. After 8 weeks of treatment, aortic rings were isolated to assess endothelium-dependent and -independent relaxation. Quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin sections. Aortic and systemic ROS levels were measured using dihydroethidine and thiobarbituric acid-reactive substances, respectively. Aortic MMP-2 levels and activity were determined by gelatin and in situ zymography, fluorimetry, and immunohistochemistry. Tempol and apocyanin attenuated 2K-1C hypertension (181+/-20.8 and 192+/-17.6 mm Hg, respectively, versus 213+/-18 mm Hg in hypertensive controls; both p<0.05) and prevented the reduction in endothelium-dependent vasorelaxation found in 2K-1C rats. Tempol, but not apocyanin (p>0.05), prevented the vascular remodeling found in 2K-1C rats (all p<0.01). Tempol was more effective than apocyanin in attenuating hypertension-induced increases in oxidative stress (both p<0.05), MMP-2 levels, and MMP-2 activity in hypertensive rats (all p<0.05). Our results suggest that antioxidant approaches decrease MMP-2 upregulation and attenuate the vascular dysfunction and remodeling during 2K-1C hypertension.
Castro
Michele M
MM
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of São Paulo, Ribeirao Preto, SP, Brazil.
Rizzi
Elen
E
Rodrigues
Gerson J
GJ
Ceron
Carla S
CS
Bendhack
Lusiane M
LM
Gerlach
Raquel F
RF
Tanus-Santos
Jose E
JE
D000098:Acetophenones / Q000008:administration & dosage*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001795:Blood Pressure Determination; D003497:Cyclic N-Oxides / Q000008:administration & dosage*; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000378:metabolism; D006978:Hypertension, Renovascular / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012077:Renal Artery / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D013113:Spin Labels; D013858:Thiobarbiturates / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000098:Acetophenones; D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D013858:Thiobarbiturates; C514241:dihydroethidine; D003997:Dicarbethoxydihydrocollidine; C056165:acetovanillone; D020778:Matrix Metalloproteinase 2; C029684:thiobarbituric acid; C001803:tempol