Structure, endothelial function, cell growth, and inflammation in blood vessels of angiotensin II-infused rats: role of peroxisome proliferator-activated receptor-gamma.
BACKGROUND
Pioglitazone and rosiglitazone, thiazolidinedione peroxisome proliferator-activated receptor-gamma (PPARgamma) activators, reduce blood pressure (BP) in some hypertensive models by unclear mechanisms. We tested the hypothesis that pioglitazone or rosiglitazone would prevent BP elevation and vascular dysfunction in angiotensin (Ang) II-infused rats by direct vascular effects.


RESULTS
Sprague-Dawley rats received Ang II (120 ng x kg(-1) x min(-1) SC) with or without pioglitazone (10 mg x kg(-1) x d(-1)) or rosiglitazone (5 mg x kg(-1) x d(-1)) for 7 days. Systolic BP, elevated in Ang II-infused rats (176+/-5 mm Hg) versus controls (109+/-2 mm Hg, P<0.01), was reduced by pioglitazone (134+/-2 mm Hg) or rosiglitazone (123+/-2 mm Hg). In mesenteric small arteries studied in a pressurized myograph, media/lumen ratio was increased (P<0.05) and acetylcholine-induced relaxation impaired in Ang II-infused rats (P<0.05); both were normalized by the thiazolidinediones. In Ang II-infused rats, vascular DNA synthesis (by 3H-thymidine incorporation); expression of cell cycle proteins cyclin D1 and cdk4, angiotensin II type 1 receptors, vascular cell adhesion molecule-1, and platelet and endothelial cell adhesion molecule; and nuclear factor-kappaB activity were increased. These changes were abrogated by pioglitazone or rosiglitazone.


CONCLUSIONS
Thiazolidinedione PPAR-gamma activators attenuated the development of hypertension, corrected structural abnormalities, normalized cell growth, and improved endothelial dysfunction induced by Ang II and prevented upregulation of angiotensin II type 1 receptors, cell cycle proteins, and proinflammatory mediators. Thiazolidinediones may be useful in the prevention and/or treatment of hypertension, particularly when it is associated with insulin resistance or diabetes mellitus.
Diep
Quy N
QN
Canadian Institutes of Health Research Multidisciplinary Research Group on Hypertension, Montreal, Quebec, Canada.
El Mabrouk
Mohammed
M
Cohn
Jeffrey S
JS
Endemann
Dierk
D
Amiri
Farhad
F
Virdis
Agostino
A
Neves
Mario Fritsch
MF
Schiffrin
Ernesto L
EL
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D007279:Injections, Subcutaneous; D008055:Lipids / Q000097:blood; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis; D000077205:Pioglitazone; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012083:Renin / Q000097:blood; D000077154:Rosiglitazone; D013844:Thiazoles / Q000008:administration & dosage; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D018797:Cell Cycle Proteins; D008055:Lipids; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011945:Receptors, Angiotensin; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D000804:Angiotensin II; D000450:Aldosterone; D003094:Collagen; D004247:DNA; D012083:Renin; D000077205:Pioglitazone