Activation of Adenosine Monophosphate-activated Protein Kinase by Telmisartan Decreases Basal and Platelet-derived Growth Factor-stimulated Vascular Smooth Muscle Cell Proliferation via Inhibiting the Mammalian Target of Rapamycin/p70 S6 Kinase Signaling Axis

Abstract

Background: Telmisartan, an angiotensin II type 1 receptor blocker (ARB), is widely used to treat hypertension by blocking the renin-angiotensin-aldosterone system. Although abnormal proliferation of vascular smooth muscle cells (VSMCs) is a well-established contributor to the development of various vascular diseases, such as atherosclerosis, the effect of telmisartan on VSMC proliferation and its mechanism of action have not been fully revealed. Herein, we investigated the molecular mechanism whereby telmisartan inhibits rat VSMC proliferation. Methods: We measured VSMC proliferation by MTT assay, and performed inhibitor studies and western blot analyses using basal and platelet-derived growth factor (PDGF)-stimulated rat VSMCs. To elucidate the role of AMP-activated protein kinase (AMPK), we introduced dominant-negative (dn)-AMPKα1 gene into VSMCs. Results: Telmisartan decreased VSMC proliferation, which was accompanied by decreased phosphorylations of mammalian target of rapamycin (mTOR) at Ser2448 (p-mTOR-Ser 2448) and p70 S6 kinase (p70S6K) at Thr389 (p-p70S6K-Thr 389) in dose-and time-dependent manners. Telmisartan dose-and time-dependently increased phosphorylation of AMPK at Thr172 (p-AMPK-Thr 172). Co-treatment with compound C, a specific AMPK inhibitor, or ectopic expression of the dn-AMPKα1 gene, significantly reversed telmisartan-inhibited VSMC proliferation, p-mTOR-Ser 2448 and p-p70S6K-Thr 389 levels. Among the ARBs tested (including losartan and fimasartan), only telmisartan increased p-AMPK-Thr 172 and decreased p-mTOR-Ser 2448 , p-p70S6K-Thr 389 , and VSMC proliferation. Furthermore, GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ (PPARγ) antagonist, did not affect any of the telmisartan-induced changes. Finally, telmisartan also exhibited inhibitory effects on VSMC proliferation by increasing p-AMPK-Thr 172 and decreasing p-mTOR-Ser 2448 and p-p70S6K-Thr 389 in a PDGF-induced in vitro atherosclerosis model. Conclusion: These results demonstrated that telmisartan-activated AMPK inhibited basal and PDGF-stimulated VSMC proliferation, at least in part, by downregulating the mTOR/p70S6K signaling axis in a PPARγ-independent manner. These observations suggest that telmisartan could be used to treat arterial narrowing diseases such as atherosclerosis and restenosis.

Human monocyte-derived suppressive cells (HuMoSC) for cell therapy in giant cell arteritis

“…The other plausible explanation, not inconsistent with the first, is that HuMoSCs (or their supernatant) could inhibit the mTOR complex by acting on another PDGF-activated pathway, such as AMP-activated protein kinase (AMPK). Indeed, telmisartan has been shown to inhibit rat VSMC proliferation via AMPK-dependent inhibition of mTOR phosphorylation ( 34 ). Along this line, another study demonstrated that jujuboside B antagonizes PDGF-BB-induced phenotypic switch, proliferation and migration of VSMCs partly through AMPK/PPAR-γ pathway ( 35 ).…”

Far-Infrared Irradiation Decreases Proliferation in Basal and PDGF-Stimulated VSMCs Through AMPK-Mediated Inhibition of mTOR/p70S6K Signaling Axis

“…Rat aortic VSMCs were isolated and cultured as previously described. 25 Briefly, six-week-old male Sprague-Dawley (SD) rats were euthanized with CO 2 gas and subsequent cervical dislocation, and their thoracic aortas were immediately dissected. Connective tissues were removed, and the endothelium was denuded by gentle rubbing.…”

“… 19 20 Of the many downstream targets of AMPK, the mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) signaling pathway responsible for the regulation of protein synthesis, cell proliferation, and metabolism 19 21 is blocked when AMPK is activated, leading to the inhibition of cell proliferation in various types of cells. 22 23 24 25 A recent study reported that activation of AMPK by telmisartan, an angiotensin II type 1 receptor blocker, decreases basal and PDGF-stimulated VSMC proliferation via inhibiting the mTOR/p70S6K signaling pathway. 25 Nevertheless, no study has been reported on whether FIR irradiation inhibits VSMC proliferation and the AMPK/mTOR/p70S6K signaling axis.…”

“…22 23 24 25 A recent study reported that activation of AMPK by telmisartan, an angiotensin II type 1 receptor blocker, decreases basal and PDGF-stimulated VSMC proliferation via inhibiting the mTOR/p70S6K signaling pathway. 25 Nevertheless, no study has been reported on whether FIR irradiation inhibits VSMC proliferation and the AMPK/mTOR/p70S6K signaling axis.…”

Mammalian Target of Rapamycin as the Therapeutic Target of Vascular Proliferative Diseases: Past, Present, and Future

“…12 Lu et al found that nesfatin-1, a multifunctional adipocytokine, promotes VSMC proliferation by activating the PI3K/Akt/mTOR signaling pathway and plays a key regulatory role in hypertension and vascular remodeling. 109 In addition, a study showed that tanshinone I, a cardiovascular therapeutic agent, inhibits VSMC proliferation by inhibiting the PI3K/mTOR signaling pathway, facilitating the treatment of vascular diseases such as hypertension. 110 These results suggest that mTOR is implicated in the development and progression of hypertension, and mTOR-mediated VSMC proliferation plays a role in hypertension.…”