AUTHOR=Xu Lirong , Liu Yutong , Cheng Qianyun , Shen Yang , Yuan Ye , Jiang Xiaolang , Li Xu , Guo Daqiao , Jiang Junhao , Lin Changpo 

TITLE=Bmal1 Downregulation Worsens Critical Limb Ischemia by Promoting Inflammation and Impairing Angiogenesis

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.712903

DOI=10.3389/fcvm.2021.712903

ISSN=2297-055X

ABSTRACT=Critical limb ischemia (CLI) is the most advanced clinical stage of peripheral vascular disease with high mobility and mortality. CLI patients suffer from lower extremity rest pain, ulceration and gangrene caused by insufficient blood and oxygen supply. Seeking for effective biomarkers and therapeutic targets is of great significance for improving the life quality of CLI patients. Circadian clock has been reported to be involved in the progression of kinds of cardiovascular diseases. Whether and how circadian genes plays a role in CLI remains unknown. In this study, by collecting femoral artery and muscle specimens of CLI patients who underwent amputation, we confirmed that circadian gene Bmal1 is downregulated in the CLI femoral artery and ischemic distal lower limb muscle. Furthermore, we verified that Bmal1 affects CLI by regulating lipids metabolism, inflammation and angiogenesis. Hind-limb ischemia model performed in WT and Bmal1-/- mice confirmed that Bmal1 disruption would lead to impaired angiogenesis. In vitro experiments indicated that decreased expression of Bmal1 would increase ox-LDL uptake and impair the endothelial cell functions, including proliferation, migration and tube formation. As for mechanisms, Bmal1 represses inflammation by inhibiting lipids uptake and by activating IL-10 transcription, and promotes angiogenesis by transcriptionally regulating VEGF expression. In conclusion, we provide evidence that circadian gene Bmal1 plays an important role in CLI by inhibiting inflammation and promoting angiogenesis. Thus, Bmal1 may be an effective biomarker and a potential therapeutic target in CLI.