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- Title
High-Density Lipoproteins Rescue Diabetes-Impaired Angiogenesis via Scavenger Receptor Class B Type I.
- Authors
Tan, Joanne T. M.; Prosser, Hamish C. G.; Dunn, Louise L.; Vanags, Laura Z.; Ridiandries, Anisyah; Tsatralis, Tania; Leece, Laura; Clayton, ZoëE.; Yuen, Sui Ching G.; Robertson, Stacy; Lam, Yuen Ting; Celermajer, David S.; Ng, Martin K. C.; Bursill, Christina A.; Lecce, Laura
- Abstract
Disordered neovascularization and impaired wound healing are important contributors to diabetic vascular complications. We recently showed that high-density lipoproteins (HDLs) enhance ischemia-mediated neovascularization, and mounting evidence suggests HDL have antidiabetic properties. We therefore hypothesized that HDL rescue diabetes-impaired neovascularization. Streptozotocin-induced diabetic mice had reduced blood flow recovery and neovessel formation in a hindlimb ischemia model compared with nondiabetic mice. Reconstituted HDL (rHDL) infusions in diabetic mice restored blood flow recovery and capillary density to nondiabetic levels. Topical rHDL application rescued diabetes-impaired wound closure, wound angiogenesis, and capillary density. In vitro, rHDL increased key mediators involved in hypoxia-inducible factor-1α (HIF-1α) stabilization, including the phosphoinositide 3-kinase/Akt pathway, Siah1, and Siah2, and suppressed the prolyl hydroxylases (PHD) 2 and PHD3. rHDL rescued high glucose-induced impairment of tubulogenesis and vascular endothelial growth factor (VEGF) A protein production, a finding associated with enhanced phosphorylation of proangiogenic mediators VEGF receptor 2 and endothelial nitric oxide synthase. Siah1/2 small interfering RNA knockdown confirmed the importance of HIF-1α stability in mediating rHDL action. Lentiviral short hairpin RNA knockdown of scavenger receptor class B type I (SR-BI) in vitro and SR-BI(-/-) diabetic mice in vivo attenuated rHDL rescue of diabetes-impaired angiogenesis, indicating a key role for SR-BI. These findings provide a greater understanding of the vascular biological effects of HDL, with potential therapeutic implications for diabetic vascular complications.
- Subjects
HIGH-density lipoprotein receptors; DIABETIC angiopathies; NEOVASCULARIZATION; SCAVENGER receptors (Biochemistry); STREPTOZOTOCIN; HYPOXIA-inducible factor 1; PHOSPHOINOSITIDES; VASCULAR endothelial growth factors; ENZYME metabolism; ANIMAL experimentation; BIOLOGICAL models; BLOOD circulation; BLOOD sugar; CELL lines; CELL receptors; CHOLESTEROL; DIABETES; ENZYMES; HIGH density lipoproteins; IMMUNOHISTOCHEMISTRY; LOW density lipoproteins; MICE; WOUND healing; NUCLEAR proteins; THERAPEUTICS
- Publication
Diabetes, 2016, Vol 65, Issue 10, p3091
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db15-1668