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

We investigated the ability of angiotensin II type 1 (AT1) receptor blockers with peroxisome proliferator-activated receptor (PPAR)-gamma agonist activity ( telmisartan and irbesartan) and AT1 receptor blockers devoid of PPAR gamma 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 PPAR gamma in the antiproliferative effects of telmisartan, we studied genetically engineered NIH3T3 cells that express PPAR gamma. Pioglitazone inhibited proliferation of NIH3T3 cells expressing PPAR gamma but had little effect on control NIH3T3 cells that lack PPAR gamma. In contrast, telmisartan inhibited proliferation equally in NIH3T3 with and without PPAR gamma. 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 PPAR gamma 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 PPAR gamma, 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 PPAR gamma. 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 PPAR gamma. (Hypertension. 2009; 54: 1353-1359.)