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Vasculoprotective effects of rosiglitazone through modulating renin-angiotensin system in vivo and vitro.

AbstractBACKGROUND:
The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone has been suggested to exert cardiovascular protection through the improvement of lipid metabolism, anti-inflammation, anti-proliferation etc. However, whether renin-angiotensin system (RAS) is involved in the vascular protective effects of PPARγ agonists is not fully understood. The present study aimed to investigate the effects of the renin-angiotensin system in vascular protection mediated by PPARγ agonists.
OBJECTIVE:
To investigate the actions of the renin-angiotensin system in vascular protection mediated by activation of PPARγ in vivo and in vitro.
METHODS:
Rats were fed a regular diet (n = 8), a cholesterol-rich diet plus methylthiouracil (80 mg/Kg/day, n = 10), a cholesterol-rich diet plus methylthiouracil and rosiglitazone (4 mg/kg/day, n = 10). The rosiglitazone treatment was started from one month after the start of cholesterol-rich diet plus methylthiouracil, and lasted five months. Cultured vascular smooth muscle cells (VSMCs) were pretreated with 1 μmol/L angiotensin II (ANG II) for 6 h and randomly divided into the control group; the ANG II group (1 μmol/L ANG II); the groups respectively treated with different concentration rosiglitazone (20, 30, 50) μmol/L for 12 h; the groups treated with 30 μmol/L rosiglitazone for (6, 12, 24) h. Morphology changes of the aortic tissues were observed by hematoxylin and eosin stain. The VSMC growth was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Angiotensin II and expression of angiotensin receptors were determined by radioimmunoassay, reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry.
RESULTS:
After 6 months, lipid deposition, VSMC proliferation and migration toward intima were observed in aortic tissues in the rats on a cholesterol-rich diet plus methylthiouracil, while these pathological changes induced by the cholesterol-rich diet were significantly suppressed by rosiglitazone. In addition, VSMC proliferation induced by ANG II was markedly inhibited by rosiglitazone. Rosiglitazone markedly down-regulated expression of angiotensin type 1 receptor (AT1R) and up-regulated expression of angiotensin type 2 receptor (AT2R) in the aortic tissues and ANG II-treated VSMCs.
CONCLUSIONS:
The present study demonstrated that PPARγ agonist rosiglitazone suppressed ANG II-induced VSMC proliferation in vitro and early atherosclerotic formation evoked by cholesterol-rich diet in vivo. These vasculoprotective effects of rosiglitazone were mediated at least partially by reduction in local tissue ANG II concentration, down-regulation of AT1R expression and up-regulation of AT2R expression both at the mRNA and protein levels.
AuthorsLiqun Ren, Naifeng Liu, Hong Zhi, Yingjuan Li, Yanzhi Li, Rining Tang, Zulong Sheng
JournalCardiovascular diabetology (Cardiovasc Diabetol) Vol. 10 Pg. 10 (Jan 26 2011) ISSN: 1475-2840 [Electronic] England
PMID21269478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cardiovascular Agents
  • Lipids
  • PPAR gamma
  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Thiazolidinediones
  • Rosiglitazone
  • Angiotensin II
Topics
  • Angiotensin II (blood)
  • Animals
  • Aortic Diseases (etiology, metabolism, pathology, prevention & control)
  • Atherosclerosis (etiology, metabolism, pathology, prevention & control)
  • Blotting, Western
  • Cardiovascular Agents (pharmacology)
  • Cell Proliferation (drug effects)
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hypercholesterolemia (complications, drug therapy, metabolism, pathology)
  • Immunohistochemistry
  • Lipids (blood)
  • Male
  • Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
  • Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
  • PPAR gamma (agonists, metabolism)
  • RNA, Messenger (metabolism)
  • Radioimmunoassay
  • Rats
  • Rats, Inbred WKY
  • Rats, Sprague-Dawley
  • Receptor, Angiotensin, Type 1 (drug effects, genetics, metabolism)
  • Receptor, Angiotensin, Type 2 (drug effects, genetics, metabolism)
  • Renin-Angiotensin System (drug effects)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rosiglitazone
  • Thiazolidinediones (pharmacology)
  • Time Factors

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