Effects of TH-142177 on angiotensin II-induced proliferation, migration and intracellular signaling in vascular smooth muscle cells and on neointimal thickening after balloon injury

• Published in: Life sciences (1973) Vol. 64; no. 22; pp. 2061 - 2070
• Main Authors: Nozawa, Yoshihisa, Matsuura, Naosuke, Miyake, Hidekazu, Yamada, Shizuo, Kimura, Ryohei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 1999
• Subjects: 1-Sarcosine-8-Isoleucine Angiotensin II - metabolism; angiotensin II; Angiotensin II - pharmacology; Angiotensin Receptor Antagonists; Animals; Arteriosclerosis - drug therapy; Carotid Artery Injuries; Carotid Artery, Common - drug effects; Carotid Artery, Common - metabolism; Catheterization - adverse effects; Cell Division - drug effects; Cell Movement - drug effects; Cells, Cultured; Glycine - analogs & derivatives; Glycine - pharmacology; Hyperplasia; Male; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 1 - metabolism; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; neointimal thickening; proliferation; protein kinase C; Protein Kinase C - metabolism; Proto-Oncogene Proteins p21(ras) - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Signal Transduction - drug effects; Tetrazoles - pharmacology; TH-142177; VSMC migration; mitogen-activated protein kinase; proliferation; angiotensin II; TH-142177; neointimal thickening; VSMC migration; protein kinase C
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(99)00153-8

We investigated the effects of TH-142177 (N-n-butyl-N-[2′-(1-H-tetrazole-5-yl) biphenyl-4-yl]-methyl-(N-carboxymethyl-benzylamino)-acetamide), a novel selective antagonist of angiotensin II type 1-receptor (AT1-R) on angiotensin II (AII)-induced proliferation and migration of vascular smooth muscle cells (VSMC), and on neointimal formation in the rat carotid artery after balloon injury, and on the intracellular signaling by the stimulation of AT1-R. High affinity AII receptor sites were detected in rat VSMC by the use of [
125I]Sar
1,Ile
8-AII. TH-142177 and losartan competed with [
125I]Sar
1,Ile
8-AII for the binding sites in VSMC in a monophasic manner, although PD123177, a selective antagonist of angiotensin II type 2-receptor (AT2-R), had little inhibitory effect, demonstrating the predominant existence of AT1-R in rat VSMC. TH-142177 prevented AII-induced DNA synthesis and migration, with a significant inhibition of 74 and 55%, respectively, at the concentration of 100 nM. AII-induced activation of p21
ras, mitogen-activated protein kinase (p42
MAPK and p44
MAPK), and protein kinase C was significantly (50–78%) inhibited by TH-142177 (100 nM), suggesting that the activation of these enzymes is mediated through the stimulation of AT1-R. Balloon-injured left carotid arteries in rats showed extensive neointimal thickening, and TH-142177 (3 mg/kg) brought out a marked decrease in the neointimal thickening after balloon injury. In conclusion, TH-142177 inhibited AII-induced proliferation and migration of rat VSMC and neointimal formation in the carotid artery after balloon injury, and these effects may be related, in part, to the suppression of ras, p42
MAPK and p44
MAPK, and protein kinase C activities through the blockade of AT1-R. Thus, TH-142177 may have therapeutic potential for the treatment of vascular diseases such as atherosclerosis and restenosis.