Key result
Telmisartan inhibits vascular smooth muscle proliferation independently of AT1 receptors and PPARgamma, unlike valsartan.
Why the study?
Does telmisartan inhibit vascular cell proliferation and AKT signaling independently of AT1 receptor blockade and PPARγ activation in cultured vascular smooth muscle and endothelial cells?
Does telmisartan inhibit vascular cell proliferation and AKT signaling independently of AT1 receptor blockade and PPARγ activation in cultured vascular smooth muscle and endothelial cells?
Telmisartan inhibits vascular smooth muscle cell proliferation and AKT activation via a novel mechanism independent of both AT1 receptor blockade and PPARγ activation, distinguishing it from other ARBs like valsartan.
Answers are grounded in this paper and cite their sources.
Does not support preferential telmisartan use in hypertension; leaves open whether off-target vascular effects differ among ARBs in vivo.
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 PPARgamma 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 PPARgamma in the antiproliferative effects of telmisartan, we studied genetically engineered NIH3T3 cells that express PPARgamma. Pioglitazone inhibited proliferation of NIH3T3 cells expressing PPARgamma but had little effect on control NIH3T3 cells that lack PPARgamma. In contrast, telmisartan inhibited proliferation equally in NIH3T3 with and without PPARgamma. 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 PPARgamma 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 PPARgamma, 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 PPARgamma. 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 PPARgamma.
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Yamamoto et al. (2009) studied Vascular cell proliferation / atherosclerosis (preclinical models). Telmisartan (and irbesartan) vs. Valsartan, eprosartan (up to 80 µM), pioglitazone (10 µM positive control), and DMSO vehicle control was evaluated on Inhibition of vascular cell proliferation (cell numbers counted via hemacytometer) and relative phosphorylation of AKT (Thr308) and ERK1/2. Telmisartan dose-dependently inhibited vascular smooth muscle cell proliferation and AKT phosphorylation starting at 2.5–5 µM independently of AT1 receptors and PPARγ, whereas valsartan had no effect.
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