Atorvastatin and sildenafil decrease vascular TGF-β levels and MMP-2 activity and ameliorate arterial remodeling in a model of renovascular hypertension.
Imbalanced matrix metalloproteinase (MMP)-2 activity and transforming growth factor expression (TGF-β) are involved in vascular remodeling of hypertension. Atorvastatin and sildenafil exert antioxidant and pleiotropic effects that may result in cardiovascular protection. We hypothesized that atorvastatin and sildenafil alone or in association exert antiproliferative effects by down-regulating MMP-2 and TGF-β, thus reducing the vascular hypertrophy induced by two kidney, one clip (2K1C) hypertension. Sham and 2K1C rats were treated with oral atorvastatin 50 mg/kg, sildenafil 45 mg/kg, or both, daily for 8 weeks. Blood pressure was monitored weekly. Morphologic changes in the aortas were studied. TGF-β levels were determined by immunofluorescence. MMP-2 activity and expression were determined by in situ zymography, gel zymography, Western blotting, and immunofluorescence. The effects of both drugs on proliferative responses of aortic smooth muscle cells to PDGF and on on MMP-2 activity in vitro were determined. Atorvastatin, sildenafil, or both drugs exerted antiproliferative effects in vitro. All treatments attenuated 2K1C-induced hypertension and prevented the increases in the aortic cross-sectional area and media/lumen ratio in 2K1C rats. Aortas from 2K1C rats showed higher collagen deposition, TGF-β levels and MMP-2 activity and expression when compared with Sham-operated animals. Treatment with atorvastatin and/or sildenafil was associated with attenuation of 2K1C hypertension-induced increases in these pro-fibrotic factors. However, these drugs had no in vitro effects on hr-MMP-2 activity. Atorvastatin and sildenafil was associated with decreased vascular TGF-β levels and MMP-2 activity in renovascular hypertensive rats, thus ameliorating the vascular remodeling. These novel pleiotropic effects of both drugs may translate into protective effects in patients.
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil.
Danielle A
DA
Guimarães
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil.
Elen
E
Rizzi
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil.
Carla S
CS
Ceron
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil.
Alisson
A
Martins-Oliveira
Department of Morphology, Estomatology and Physiology, Dental School of Ribeirao Preto, University of Sao Paulo, Brazil.
Raquel F
RF
Gerlach
Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Sruti
S
Shiva
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil. Electronic address: tanus@fmrp.usp.br.
Jose E
JE
Tanus-Santos
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000069059:Atorvastatin / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling
D002317:Cardiovascular Agents; D004338:Drug Combinations; D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D003094:Collagen; D000069059:Atorvastatin; D000068677:Sildenafil Citrate; D020778:Matrix Metalloproteinase 2
Atorvastatin; Hypertension; Matrix metalloproteinase; Sildenafil