PPAR-gamma inhibits ANG II-induced cell growth via SHIP2 and 4E-BP1.
The present study evaluated the effects of peroxisome proliferator-activated receptor (PPAR)-gamma 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-gamma activators 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) or rosiglitazone. Both 15d-PGJ2 and rosiglitazone decreased ANG II-induced DNA synthesis. Rosiglitazone treatment increased nuclear PPAR-gamma expression and activity in VSMC. However, rosiglitazone did not alter expression of PPAR-alpha/beta, 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-gamma activation reduced ANG II-induced growth associated with inhibition of ERK 1/2, Akt, 4E-BP1, and SHIP2. Modulation of these pathways by PPAR-gamma activators may contribute to regression of vascular remodeling in hypertension.
Benkirane
Karim
K
Clinical Institute of Health Research Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
Amiri
Farhad
F
Diep
Quy N
QN
El Mabrouk
Mohammed
M
Schiffrin
Ernesto L
EL
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D047495:PPAR gamma / Q000096:biosynthesis / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000187:drug effects; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins; D010744:Phosphoric Monoester Hydrolases; D015230:Prostaglandin D2; D051057:Proto-Oncogene Proteins c-akt; D011945:Receptors, Angiotensin; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D013936:Thymidine; C477819:15-deoxyprostaglandin J2; C499526:Eif4ebp1 protein, rat; C098706:INPPL1 protein, human