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

Seo Young Kwak,Seungbum Lee,Sehwan Shim,Hyewon Kim,Ah Ra Kim,Sun-Joo Lee,Won Il Jang,Eun Hye Kim,Min-Jung Kim,Won-Suk Jang,Hyosun Jang,Sunhoo Park

doi:10.3390/ijms22041828

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.

Highlights

IntroductionRadiation affects numerous types of normal ‘healthy’ tissues surrounding the targeted tumor tissue
We investigated whether atorvastatin could influence the invasion capacity in irradiated endothelial cells
Irradiated human umbilical vein endothelial cells (HUVECs) demonstrated reduced invasive ability compared with the control group, atorvastatin treatment dramatically increased the number of invasive endothelial cells after irradiation (Figure 1B)

Summary

Introduction

Radiation affects numerous types of normal ‘healthy’ tissues surrounding the targeted tumor tissue. Exposure of the intestine to radiation can cause severe damage to epithelial, endothelial, and neuronal cells, resulting in radiation-induced enteropathy [3,4,5,6]. Individuals with radiation-induced enteropathy frequently develop clinical symptoms, such as diarrhea, vomiting, fatigue, nutritional deficiency, and rectal bleeding [7,8,9]. These are serious clinical concerns, there are no FDA-approved drugs for radiation-induced enteropathy

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Conclusion