Atorvastatin Inhibits Endothelial PAI-1-Mediated Monocyte Migration and Alleviates Radiation-Induced Enteropathy

Abstract

Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.

The protective role of statins in COVID-19 patients: a retrospective observational study

“…Statins cause a notable downregulation of coagulation cascade due to reduced tissue factor expression, reduced thrombin formation, and fibrinogen cleavage. Statins upregulate the endothelial function and antagonize the COVID-19 induced endothelial effects by attenuating VEGF and serum PAI-1 levels [ 47 – 49 ]. This positive effect of statins on the coagulation cascade is shown by lower circulating D-dimer levels, as observed in our study.…”

Radioprotective countermeasures for radiation injury (Review)

“…p53 is closely associated with radiosensitivity and radiation-induced cell death; notably, statins can target the p53-controlled mevalonate pathway, thereby reducing the risk of cancer (59,60). The IR-induced expression of proinflammatory and profibrotic marker genes was revealed to be attenuated by statins in vitro and in vivo (61)(62)(63). These effects were mediated by the attenuation of Rho signaling.…”

Phytosterols Alleviate Hyperlipidemia by Regulating Gut Microbiota and Cholesterol Metabolism in Mice

“…The mechanism of HLP is related to the abnormal transportation and metabolism of adipose that makes one or more lipids in serum to be higher than normal, which is char-acterized by increased total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) and decreased high-density lipoprotein cholesterol (HDL-C) in serum [3]. Currently, statins are the most widely used and effective drugs in the clinical treatment of HLP, which can reduce intracellular cholesterol synthesis by competitively inhibiting hydroxy-3-methylglutaryl-coenzyme A reductase activity [4]. Nevertheless, the use of statins has its limitations and side effects such as hepatotoxicity, rhabdomyolysis, and skeletal muscle damage [5][6][7].…”