Telmisartan-induced inhibition of vascular cell proliferation beyond angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma activation.
Telmisartan-induced inhibition of vascular cell proliferation beyond angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma activation.
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DOI：
10.1161/hypertensionaha.109.138750
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发表时间：
2009-12
期刊：
影响因子：
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通讯作者：
Rakugi H
中科院分区：
文献类型：
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作者：
Yamamoto K;Ohishi M;Ho C;Kurtz TW;Rakugi H
我们研究了具有 PPARγ 激动剂活性的 ARB（替米沙坦和厄贝沙坦）和缺乏 PPARγ 激动剂活性的 ARB（依普罗沙坦和缬沙坦）在没有血管紧张素 II 刺激的情况下抑制血管细胞增殖的能力。替米沙坦和厄贝沙坦在较小程度上以剂量依赖性方式抑制人主动脉血管平滑肌细胞的增殖，而依普罗沙坦和缬沙坦则不然。为了研究 PPARγ 在替米沙坦抗增殖作用中的作用，我们研究了表达 PPARγ 的基因工程 NIH3T3 细胞。吡格列酮抑制表达 PPARγ 的 NIH3T3 细胞增殖，但对缺乏 PPARγ 的对照 NIH3T3 细胞影响不大。相比之下，替米沙坦在有或没有 PPARγ 的情况下对 NIH3T3 的增殖抑制作用相同。缬沙坦未能抑制任一细胞系的增殖。此外，替米沙坦对平滑肌 PPARγ 靶向敲除小鼠和对照小鼠的主动脉平滑肌细胞的增殖抑制作用相同，而缬沙坦对细胞增殖没有影响。替米沙坦但不是缬沙坦，降低了 AKT 的磷酸化，但不降低 ERK 的磷酸化，否则是通过暴露于静止的人平滑肌细胞、缺乏 PPARγ 的静止小鼠平滑肌细胞或缺乏 AT1 受体的静止 CHO-K1 细胞的血清而诱导的。总之，在没有外源补充血管紧张素 II 的情况下，替米沙坦的抗增殖作用不仅仅涉及 AT1 受体阻断，而且不需要激活 PPARγ。可能推测 AKT 激活的抑制是介导替米沙坦抗增殖作用的机制，包括在缺乏 AT1 受体或 PPARγ 的细胞中。
We investigated the ability of ARBs with PPARγ agonist activity (telmisartan and irbesartan), and ARBs 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 smooth muscle and from control mice whereas valsartan had no effect on cell proliferation. Telmisartan but not valsartan, reduced phosphorylation of AKT but not ERK otherwise induced by exposure to serum of either quiescent human smooth muscle cells, quiescent mice smooth muscle cells lacking PPARγ or quiescent CHO-K1 cells lacking AT1 receptor. In summary, the antiproliferative effect 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.