Simvastatin promotes cardiac microvascular endothelial cells proliferation, migration and survival by phosphorylation of p70 S6K and FoxO3a

Abstract

Restenosis severely limits the overall efficacy of interventions. One of the reasons is the lack of reendothelialization related to inhibition of endothelial cell proliferation and migration since drug is delivered to the luminal surface. Statins can promote angiogenic processes by improving endothelial function, proliferation and migration in cardiac microvascular endothelial cells (CMECs). This study clarified the effect of simvastatin on Akt/mTOR/p70 S6K and FoxO3a signalling pathways in rat CMECs following pretreated with rapamycin. Rapamycin treatment for 24 h inhibited CMECs' proliferation, migration and NO (nitric oxide) secretion, but with increased cell apoptosis and reactive oxygen species (ROS) production. In contrast, simvastatin pretreatment significantly improved proliferation, migration and NO secretion, and inhibited CMECs' apoptosis and ROS production in rapamycin-induced CMECs. Western blot assay showed that, after treatment with simvastatin, the phosphorylation of Akt/mTOR/p70 S6K and FoxO3a were up-regulated in rapamycin-induced CMECs, which was significantly reversed by pretreatment with LY294002. The data suggest that simvastatin inhibits rapamycin-induced CMECs dysfunction and apoptosis, probably through activation of PI3K/Akt/mTOR/p70 S6K and mTOR/FoxO3a signalling pathway in a sequential manner and this pathway may be important in some of the pleiotropic effects of statins.

Protective Effects of Fluvastatin on Reproductive Function in Obese Male Rats Induced by High-Fat Diet through Enhanced Signaling of mTOR

“…One study has found that mTOR plays crucial role in the normal spermatogenesis process and can preferentially regulate p70s6k rather than 4e-bp1 to promote cell proliferation [12,38,39]. Simvastatin has been shown to induce proliferation, migration and reduce apoptosis of endothelil cells via mTOR signaling pathways [40]. We hypothesized that fluvastatin may act through similar mechanisms on spermatogonia in our model.…”

α -Lipoic Acid-Plus Ameliorates Endothelial Injury via Inhibiting the Apoptosis Pathway Mediated by Intralysosomal Cathepsins in Vivo and Vitro Endothelial Injury Model

“…Thus, nerenone appears to provide favorable vascular effects through restoring vascular integrity and preventing adverse vascular remodeling [32]. Besides, low dosage of simvastatin can induce cardiac microvascular ECs proliferation, migration and anti-apoptosis via PI3K/Akt/mTOR/p70S6K and mTOR/FoxO3 signalling pathways, and then exert a bene cial effect by regulation of NO and ROS production in microvascular ECs [33]. In our research, we also con rmed that iron evidently aggravated ECs injury via aggravating lysosomal injury and LAP could alleviate ECs injury triggered by redox-active iron decomposed by OxyHb.…”

The O‐methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation

“…The PI3K/AKT signal pathway is considered a key regulator of cell growth, proliferation, and cell cycle progression. Phosphorylation of AKT/mTOR/P70S6K prevents dysfunction and apoptosis of cardiac microvascular endothelial cells . In many cancers, the abnormal activation of the AKT/mTOR signal prevents cells from undergoing apoptosis and maintains cell growth .…”