Peroxisome proliferator-activated receptor gamma activators downregulate angiotensin II type 1 receptor in vascular smooth muscle cells.
BACKGROUND
Peroxisome proliferator-activated receptor gamma (PPARgamma) activators, such as troglitazone (Tro), not only improve insulin resistance but also suppress the neointimal formation after balloon injury. However, the precise mechanisms have not been determined. Angiotensin II (Ang II) plays crucial roles in the pathogenesis of atherosclerosis, hypertension, and neointimal formation after angioplasty. We examined the effect of PPARgamma activators on the expression of Ang II type 1 receptor (AT(1)-R) in cultured vascular smooth muscle cells (VSMCs).


RESULTS
AT(1)-R mRNA and AT(1)-R protein levels were determined by Northern blot analysis and radioligand binding assay, respectively. Natural PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2), as well as Tro, reduced the AT(1)-R mRNA expression and the AT(1)-R protein level. The PPARgamma activators also reduced the calcium response of VSMCs to Ang II. PPARgamma activators suppressed the AT(1)-R promoter activity measured by luciferase assay but did not affect the AT(1)-R mRNA stability, suggesting that the suppression occurs at the transcriptional level.


CONCLUSIONS
PPARgamma activators reduced the AT(1)-R expression and calcium response to Ang II in VSMCs. Downregulation of AT(1)-R may contribute to the inhibition of neointimal formation by PPARgamma activators.
Takeda
K
K
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Ichiki
T
T
Tokunou
T
T
Funakoshi
Y
Y
Iino
N
N
Hirano
K
K
Kanaide
H
H
Takeshita
A
A
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D020871:RNA Stability / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000804:Angiotensin II; D000077288:Troglitazone; D015230:Prostaglandin D2; D002118:Calcium