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.
Cell-penetrating peptides (CPPs) have great potential to deliver bioactive agents into cells. Although there have been many recent advances in CPP-related research, it is still important to develop more efficient CPPs. The development of CPPs by in silico methods is a very useful addition to experimental methods, but in many cases it can lead to a large number of false-positive results. In this study, we developed a deep-learning-based CPP prediction method, AiCPP, to develop novel CPPs. AiCPP uses a large number of peptide sequences derived from human-reference proteins as a negative set to reduce false-positive predictions and adopts a method to learn small-length peptide sequence motifs that may have CPP tendencies. Using AiCPP, we found that short peptide sequences derived from amyloid precursor proteins are efficient new CPPs, and experimentally confirmed that these CPP sequences can be further optimized.
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