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PPAR- inhibits ANG II-induced cell growth via SHIP2 and 4E-BP1

Canadian Institutes of Health Research Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Montreal, Quebec, Canada

Submitted 20 June 2005 ; accepted in final form 2 September 2005

The present study evaluated the effects of peroxisome proliferator-activated receptor (PPAR)- activators on ANG II-induced signaling pathways and cell growth. Vascular smooth muscle cells (VSMC) derived from rat mesenteric arteries were treated with ANG II, with/without the AT₁ receptor blocker valsartan or the AT₂ receptor blocker PD-123319, after pretreatment for 24 h with the PPAR- activators 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂) or rosiglitazone. Both 15d-PGJ₂ and rosiglitazone decreased ANG II-induced DNA synthesis. Rosiglitazone treatment increased nuclear PPAR- expression and activity in VSMC. However, rosiglitazone did not alter expression of PPAR-/, ERK 1/2, Akt, or ANG II receptors. 15d-PGJ₂ and rosiglitazone decreased ERK 1/2 and Akt peak activity, both of which were induced by ANG II via the AT₁ receptor. Rosiglitazone inhibited ANG II-enhanced phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), as well as Src homology (SH) 2-containing inositol phosphatase 2 (SHIP2). PPAR- activation reduced ANG II-induced growth associated with inhibition of ERK 1/2, Akt, 4E-BP1, and SHIP2. Modulation of these pathways by PPAR- activators may contribute to regression of vascular remodeling in hypertension.

vascular smooth muscle cell; phosphatidylinositol 3-kinase; mitogen-activated protein kinase; 4E-binding protein 1; Src homology 2-containing inositol phosphatase 2; angiotensin II; peroxisome proliferator-activated receptor-

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