The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) in the vascular wall are crucial pathological events involved in cardiovascular impairments including hypertension, heart failure, and atherosclerosis. At the molecular level, the mammalian target of rapamycin (mTOR)-ribosomal protein S6 kinase beta-1 (p70S6K) signaling pathway is essential to potentiate VSMC proliferation and migration. Although angiotensin II receptor type 1 ­(AT1-R) antagonists such as valsartan and telmisartan have a significant cardiovascular protective effect, the molecular basis of this class of drugs in VSMC proliferation and migration remains elusive. By using cultured VSMCs, adenosine monophosphate-activated protein kinase (AMPK) α2 knockout mice, and hypertensive rat models, this study investigated whether AT1-R antagonists can inhibit the mTOR-p70S6K signaling pathway in VSMCs and the vascular wall. Valsartan activated AMPK, which in turn suppressed reactive oxygen species production and consequently attenuated VSMC proliferation and migration. In vivo, a clinical dose of telmisartan significantly inhibited the mTOR-p70S6K signaling pathway in the vascular wall of wild-type but not AMPKα2–/– mice. Furthermore, spontaneously hypertensive rats had significantly elevated phosphorylation of mTOR and p70S6K in the aorta compared to Wistar-Kyoto rats, which were reduced by telmisartan administration. These data suggest that AT1-R antagonists inhibit VSMC proliferation and migration via their regulation of AMPK, mTOR, and p70S6K, which contribute to the cardioprotective effects of these drugs.

Gout is a multifaceted inflammatory disease involving vascular impairments induced by hyperuricemia. Experiments using human umbilical vein endothelial cells treated with uric acid (UA), monosodium urate (MSU), or serum from gout patients showed increased expression of pro-inflammatory genes (ie, VCAM1, ICAM1, CYR61, CCNA1, and E2F1) with attendant increase in monocyte adhesion. Mechanistically, UA-or MSU-induced SREBP2 expression and its transcriptional activity. RNA sequencing analysis and real-time PCR showed the induction of YAP signaling and pro-inflammatory pathways in HUVECs transfected with adenovirus-SREBP2. The How to cite this article: Zhao Z, Zhao Y, Zhang Y, et al. Gout-induced endothelial impairment: The role of SREBP2 transactivation of YAP.

Valsartan (VAL), an antagonist of angiotensin II receptor type 1, has antihypertensive and multiple cardiovascular protective effects. The pleiotropic functions of VAL are related to the increased synthesis and biological activity of intravascular nitric oxide (NO). In this study, the role and mechanisms of VAL in the synthesis of NO were examined in human umbilical vein endothelial cells (HUVECs). Ten µmol/L of VAL was used to treat EA.hy926 cells for 30 minutes, 1, 3, 6, 12, and 24 hours, and three concentrations of VAL (i.e., 10, 1, and 0.1 µmol/L) were used to treat EA.hy926 cells for 24 hours. The cells were divided into five groups: control, VAL, VAL + Compound C (adenosine monophosphate-activated protein kinase [AMPK] inhibitor, 1 µmol/L), VAL + LY294002 (Akt [protein kinase B] inhibitor, 10 µmol/L), and VAL + L-nitro-arginine methyl ester (L-NAME, endothelial NO synthase [eNOS] inhibitor, 500 µmol/L) groups. The NO content in the VAL-treated HUVEC line (EA.hy926) was detected using the nitrate reductase method, and western blot was used to detect the phosphorylation of Akt, AMPK, and eNOS, as well as the changes in total protein levels. VAL increased NO synthesis in EA.hy926 cells in time- and dose-dependent manners (p < 0.05) and the intracellular phosphorylation levels of Akt, AMPK, and eNOS at the corresponding time points. LY294002, Compound C, and L-NAME could inhibit the VAL-promoted NO synthesis. VAL activated Akt, AMPK, and eNOS, thus promoting NO synthesis and playing a protective role in endothelial cells. These results partially explained the mechanisms underlying the cardiovascular protective effects of VAL.

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