Peroxisome proliferator-activated receptor gamma ligands inhibit Rho/Rho kinase pathway by inducing protein tyrosine phosphatase SHP-2.

Shu Wakino, Koichi Hayashi, Takeshi Kanda, Satoru Tatematsu, Koichiro Honma, Kyoko Yoshioka, Ichiro Takamatsu, Takao Saruta

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
JournalCirculation Research
Volume95
Issue number5
Publication statusPublished - 2004 Sep 3

Fingerprint

pioglitazone
Non-Receptor Type 11 Protein Tyrosine Phosphatase
rho-Associated Kinases
PPAR gamma
troglitazone
Ligands
Inbred SHR Rats
Inbred WKY Rats
Angiotensin II
Smooth Muscle Myocytes
Blood Vessels
Blood Pressure
Guanine Nucleotide Exchange Factors
Protein Tyrosine Phosphatases
Guanosine Triphosphate
Antihypertensive Agents
Up-Regulation
Hemodynamics
Phosphorylation
Cell Membrane

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Peroxisome proliferator-activated receptor gamma ligands inhibit Rho/Rho kinase pathway by inducing protein tyrosine phosphatase SHP-2. / Wakino, Shu; Hayashi, Koichi; Kanda, Takeshi; Tatematsu, Satoru; Honma, Koichiro; Yoshioka, Kyoko; Takamatsu, Ichiro; Saruta, Takao.

In: Circulation Research, Vol. 95, No. 5, 03.09.2004.

Research output: Contribution to journalArticle

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AU - Wakino, Shu

AU - Hayashi, Koichi

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AU - Tatematsu, Satoru

AU - Honma, Koichiro

AU - Yoshioka, Kyoko

AU - Takamatsu, Ichiro

AU - Saruta, Takao

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