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FoxO1‐Induced Inflammation Contributes to the Development of Diabetic Vascular Remodeling
Author(s) -
LIU Jingjin
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.512.2
Subject(s) - foxo1 , gene knockdown , downregulation and upregulation , inflammasome , vascular smooth muscle , diabetes mellitus , inflammation , medicine , endocrinology , nod , diabetic cardiomyopathy , biology , signal transduction , microbiology and biotechnology , heart failure , cardiomyopathy , cell culture , protein kinase b , biochemistry , genetics , smooth muscle , gene
Complications from diabetes often result in poor outcomes for patients, even after optimized interventions. Forkhead transcription factor 1 (FoxO1) is a key angiogenic regulator that plays a pathologic role in the progression of diabetes. The present study was designed to investigate the involvement of FoxO1 in the development of diabetic vascular complications and elucidate its underlying mechanisms. Comparative studies were carried out in wild‐type (WT) versus FoxO1‐selective inhibitor AS1842856 (AS)‐gavaged rats at 8 weeks after STZ injection, as well as in human aortic arterial smooth muscle cells (HASMCs). We found that AS prevented both aortic wall morphological changes in STZ‐induced diabetic rats and recruited SMCs in carotid artery media. Treatment with pharmacological inhibition or knockdown of FoxO1 prevented increases in pro‐inflammatory factors and adhesion factors, and NLRP3 (NOD‐like receptor family protein 3) inflammasome activation. Furthermore, downregulation of FoxO1 attenuated diabetes‐induced phenotypic switch both in vivo in rat carotid artery, and in vitro in human smooth muscle cells (HASMCs). FoxO1 knockdown also reversed the synergic effects of TNF‐α and high glucose responsible for inducing cellular death, NLPR3 inflammasome and HASMC phenotype switching. Furthermore, FoxO1 pharmacological inhibition restored FoxO1‐3‐phosphoinositide‐dependent protein kinase 1 (Pdk1) binding, restraining FoxO1 nuclear translocation, which served as the basis for subsequent transcriptional regulation during hyperglycemia. Taken together, our data suggest that FoxO1 is a novel promoter of vascular remodeling in STZ‐induced diabetes, and thus may have important therapeutic implications for diabetes‐caused cardiovascular diseases. Support or Funding Information The research work of the authors was supported by the Research Grants Council (RGC)/GRF grants (17158616M and 17121315M). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .