Telmisartan-Induced Inhibition of Vascular Cell Proliferation Beyond Angiotensin Receptor Blockade and Peroxisome Proliferator-Activated Receptor-γ Activation

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 54; no. 6; pp. 1353 - 1359
• Main Authors: Yamamoto, Koichi, Ohishi, Mitsuru, Ho, Christopher, Kurtz, Theodore W, Rakugi, Hiromi
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.12.2009; Lippincott Williams & Wilkins
• Subjects: Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Aorta - cytology; Arterial hypertension. Arterial hypotension; Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Atherosclerosis - pathology; Benzimidazoles - pharmacology; Benzoates - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Differentiation - drug effects; Cell Division - drug effects; CHO Cells; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cricetinae; Cricetulus; Extracellular Signal-Regulated MAP Kinases - metabolism; Humans; Medical sciences; Mice; Mice, Knockout; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; NIH 3T3 Cells; Phosphorylation - drug effects; PPAR gamma - genetics; PPAR gamma - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Umbilical Veins - cytology; Hypertension; Cell proliferation; Imidazole derivatives; Peptide hormone; angiotensin type II receptor blocker; Cardiovascular disease; PPARγ; Telmisartan; Vascular disease; Octapeptide; Benzimidazole derivatives; Atherosclerosis; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist; Angiotensin II
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.109.138750

We investigated the ability of angiotensin II type 1 (AT1) receptor blockers with peroxisome proliferator-activated receptor (PPAR)-γ agonist activity (telmisartan and irbesartan) and AT1 receptor blockers devoid of PPARγ agonist activity (eprosartan and valsartan) to inhibit vascular cell proliferation studied in the absence of angiotensin II stimulation. Telmisartan and, to a lesser extent, irbesartan inhibited proliferation of human aortic vascular smooth muscle cells in a dose-dependent fashion, whereas eprosartan and valsartan did not. To investigate the role of PPARγ in the antiproliferative effects of telmisartan, we studied genetically engineered NIH3T3 cells that express PPARγ. Pioglitazone inhibited proliferation of NIH3T3 cells expressing PPARγ but had little effect on control NIH3T3 cells that lack PPARγ. In contrast, telmisartan inhibited proliferation equally in NIH3T3 with and without PPARγ. Valsartan failed to inhibit proliferation of either cell line. In addition, telmisartan inhibited proliferation equally in aortic smooth muscle cells derived from mice with targeted knockout of PPARγ in the smooth muscle and from control mice, whereas valsartan had no effect on cell proliferation. Telmisartan, but not valsartan, reduced phosphorylation of AKT but not extracellular signal–regulated kinase otherwise induced by exposure to serum of quiescent human smooth muscle cells, quiescent mice smooth muscle cells lacking PPARγ, or quiescent Chinese hamster ovary-K1 cells lacking the AT1 receptor. In summary, the antiproliferative effects of telmisartan in the absence of exogenously supplemented angiotensin II involve more than just AT1 receptor blockade and do not require activation of PPARγ. It might be postulated that inhibition of AKT activation is a mechanism mediating the antiproliferative effects of telmisartan, including in cells lacking AT1 receptors or PPARγ.