Peroxisome proliferator-activated receptor gamma ligands inhibit Rho/Rho kinase pathway by inducing protein tyrosine phosphatase SHP-2.
Although peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have an antihypertensive effect in vivo, the precise mechanism has not been fully elucidated. We examined their effects on Rho/Rho kinase pathway, a key regulator of vascular tone. In cultured rat aortic smooth muscle cells (RASMC), Rho kinase stimulated by angiotensin II was suppressed by the pretreatment with pioglitazone and troglitazone, and these effects were explained by the inhibition of the Rho translocation to the cell membrane. We evaluated the role of Vav, a GTP/GDP exchange factor upregulating Rho kinase activity, and Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2), a protein tyrosine phosphatase that dephosphorylated Vav and subsequently inactivated Rho kinase. Both pioglitazone and troglitazone upregulated SHP-2, particularly in the cytosolic fraction, and the SHP-2-bound Vav, and reduced the phosphorylation of Vav. Furthermore, 4-week treatment with pioglitazone lowered systolic blood pressure in spontaneously hypertensive rats (SHR) and suppressed the Rho/Rho kinase activity in aortic tissues isolated from SHR. Consistently, the expression of SHP-2 was upregulated in vascular tissues from pioglitazone-treated SHR. The phosphorylated Vav was increased in SHR, compared with that in normotensive Wistar-Kyoto rats (WKY), which was mitigated by pioglitazone. Finally, both basal and angiotensin II-stimulated levels of Rho kinase activity were greater in RASMC from SHR than those from WKY, and the enhanced Rho kinase activity was blocked by pioglitazone or troglitazone in both strains. Collectively, PPARgamma ligands inhibit the Rho/Rho kinase pathway through upregulation of cytosolic SHP-2 expression and inactivation of Vav, and may contribute to the hemodynamic, in addition to metabolic, action in hypertensive metabolic syndrome. The full text of this article is available online at http://circres.ahajournals.org.
Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Shu
S
Wakino
Koichi
K
Hayashi
Takeshi
T
Kanda
Satoru
S
Tatematsu
Koichiro
K
Homma
Kyoko
K
Yoshioka
Ichiro
I
Takamatsu
Takao
T
Saruta
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D054460:rho-Associated Kinases
D018797:Cell Cycle Proteins; D002839:Chromans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047495:PPAR gamma; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D045162:Thiazolidinediones; C496620:Vav1 protein, rat; D000804:Angiotensin II; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; D020741:rho GTP-Binding Proteins; D000077288:Troglitazone; D000077205:Pioglitazone