{"title":"GSK3β 通过调节 OMA1/PGC1α 通路在高血压加剧动脉粥样硬化中的作用。","authors":"Hongjia Bao, Changyuan Wang, Yue Jin, Qiang Meng, Jingjing Wu, Qi Liu, Huijun Sun","doi":"10.1007/s10495-024-02029-1","DOIUrl":null,"url":null,"abstract":"<p><p>Atherosclerosis is closely related to endothelial dysfunction and hypertension. GSK3β is a critical regulator in atherosclerosis. This study was carried out to investigate the effects of GSK3β on hypertension exacerbating atherosclerosis in vitro and in vivo. L-NAME + HFD-ApoE<sup>-/-</sup> mice were used for this study for 12 weeks, and their endothelial dysfunction and inflammation were analyzed. Oil red O and H&E staining revealed that treatment with LiCl, an inhibitor of GSK3β, reduced atherosclerotic lesions and lipid accumulation. The levels of lipid homeostasis and oxidation stress were attenuated following LiCl administration. LiCl-treated ApoE-/- mice showed lowered blood pressure. LiCl also suppressed the expressions of Drp1, Bax, ICAM1, VCAM1 and TNF-α compared to HFD + L-NAME induced mice and oxLDL + L-NAME-treated Human aorta endothelial cell line(HAECs). LiCl treatment increased the expressions of MFN2 and Bcl2. Mitotracker-red, MitoSOX and JC-1 staining indicated that LiCl treatment reduced mitochondrial division and ROS production, increased mitochondrial ΔΨm compared to oxLDL + L-NAME-treated HAECs. The expression of OMA1 was decreased by LiCl treatment, while PGC1α expression was increased. In HAECs, we found that OMA1 knockdown increased mitochondrial function and the expression of PGC1α. We also demonstrated LiCl increased OMA1 ubiquitination compared with the Control group, thus decreased OMA1 expression. Furthermore, siOMA1 antagonized the increased protein expressions of ICAM1, VCAM1, TNF-α, Bax and Drp1, decreased the protein expressions of Bcl2 and MFN2 by siPGC1α. Taken together, we demonstrated that GSK3β could play a contributory role in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway and inhibiting mitochondrial function.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1000,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The contributory role of GSK3β in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway.\",\"authors\":\"Hongjia Bao, Changyuan Wang, Yue Jin, Qiang Meng, Jingjing Wu, Qi Liu, Huijun Sun\",\"doi\":\"10.1007/s10495-024-02029-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Atherosclerosis is closely related to endothelial dysfunction and hypertension. GSK3β is a critical regulator in atherosclerosis. This study was carried out to investigate the effects of GSK3β on hypertension exacerbating atherosclerosis in vitro and in vivo. L-NAME + HFD-ApoE<sup>-/-</sup> mice were used for this study for 12 weeks, and their endothelial dysfunction and inflammation were analyzed. Oil red O and H&E staining revealed that treatment with LiCl, an inhibitor of GSK3β, reduced atherosclerotic lesions and lipid accumulation. The levels of lipid homeostasis and oxidation stress were attenuated following LiCl administration. LiCl-treated ApoE-/- mice showed lowered blood pressure. LiCl also suppressed the expressions of Drp1, Bax, ICAM1, VCAM1 and TNF-α compared to HFD + L-NAME induced mice and oxLDL + L-NAME-treated Human aorta endothelial cell line(HAECs). LiCl treatment increased the expressions of MFN2 and Bcl2. Mitotracker-red, MitoSOX and JC-1 staining indicated that LiCl treatment reduced mitochondrial division and ROS production, increased mitochondrial ΔΨm compared to oxLDL + L-NAME-treated HAECs. The expression of OMA1 was decreased by LiCl treatment, while PGC1α expression was increased. In HAECs, we found that OMA1 knockdown increased mitochondrial function and the expression of PGC1α. We also demonstrated LiCl increased OMA1 ubiquitination compared with the Control group, thus decreased OMA1 expression. Furthermore, siOMA1 antagonized the increased protein expressions of ICAM1, VCAM1, TNF-α, Bax and Drp1, decreased the protein expressions of Bcl2 and MFN2 by siPGC1α. Taken together, we demonstrated that GSK3β could play a contributory role in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway and inhibiting mitochondrial function.</p>\",\"PeriodicalId\":8062,\"journal\":{\"name\":\"Apoptosis\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":6.1000,\"publicationDate\":\"2024-10-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Apoptosis\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1007/s10495-024-02029-1\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Apoptosis","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s10495-024-02029-1","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
The contributory role of GSK3β in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway.
Atherosclerosis is closely related to endothelial dysfunction and hypertension. GSK3β is a critical regulator in atherosclerosis. This study was carried out to investigate the effects of GSK3β on hypertension exacerbating atherosclerosis in vitro and in vivo. L-NAME + HFD-ApoE-/- mice were used for this study for 12 weeks, and their endothelial dysfunction and inflammation were analyzed. Oil red O and H&E staining revealed that treatment with LiCl, an inhibitor of GSK3β, reduced atherosclerotic lesions and lipid accumulation. The levels of lipid homeostasis and oxidation stress were attenuated following LiCl administration. LiCl-treated ApoE-/- mice showed lowered blood pressure. LiCl also suppressed the expressions of Drp1, Bax, ICAM1, VCAM1 and TNF-α compared to HFD + L-NAME induced mice and oxLDL + L-NAME-treated Human aorta endothelial cell line(HAECs). LiCl treatment increased the expressions of MFN2 and Bcl2. Mitotracker-red, MitoSOX and JC-1 staining indicated that LiCl treatment reduced mitochondrial division and ROS production, increased mitochondrial ΔΨm compared to oxLDL + L-NAME-treated HAECs. The expression of OMA1 was decreased by LiCl treatment, while PGC1α expression was increased. In HAECs, we found that OMA1 knockdown increased mitochondrial function and the expression of PGC1α. We also demonstrated LiCl increased OMA1 ubiquitination compared with the Control group, thus decreased OMA1 expression. Furthermore, siOMA1 antagonized the increased protein expressions of ICAM1, VCAM1, TNF-α, Bax and Drp1, decreased the protein expressions of Bcl2 and MFN2 by siPGC1α. Taken together, we demonstrated that GSK3β could play a contributory role in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway and inhibiting mitochondrial function.
期刊介绍:
Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.