High-Density Lipoproteins Rescue Diabetes-Impaired Angiogenesis via Scavenger Receptor Class B Type I.
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.
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia joanne.tan@hri.org.au christina.bursill@hri.org.au.
Joanne T M
JT
Tan
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia.
Hamish C G
HC
Prosser
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia.
Louise L
LL
Dunn
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia.
Laura Z
LZ
Vanags
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia.
Anisyah
A
Ridiandries
The Heart Research Institute, Sydney, Australia.
Tania
T
Tsatralis
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia.
Laura
L
Lecce
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia.
Zoë E
ZE
Clayton
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia.
Sui Ching G
SC
Yuen
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia.
Stacy
S
Robertson
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia.
Yuen Ting
YT
Lam
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
David S
DS
Celermajer
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
Martin K C
MK
Ng
The Heart Research Institute, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, Australia joanne.tan@hri.org.au christina.bursill@hri.org.au.
Christina A
CA
Bursill
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003921:Diabetes Mellitus, Experimental; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D008075:Lipoproteins, HDL / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*; D000098563:Seven in Absentia Proteins
D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008075:Lipoproteins, HDL; D009687:Nuclear Proteins; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins