High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor class B type I

Tan, J. T.M. et al. (2016) High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor class B type I. Diabetes, 65(10), pp. 3091-3103. (doi: 10.2337/db15-1668) (PMID:27284113)

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.

• Item Type: Articles
• Additional Information: A correction to this article is available at https://doi.org/10.2337/db17-er04b.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Robertson, Dr Stacy
• Authors: Tan, J. T.M., Prosser, H. C.G., Dunn, L. L., Vanags, L. Z., Ridiandries, A., Tsatralis, T., Lecce, L., Clayton, Z. E., Yuen, S. C. G., Robertson, S., Lam, Y. T., Celermajer, D. S., Ng, M. K.C., and Bursill, C. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Diabetes
• Publisher: American Diabetes Association
• ISSN: 0012-1797
• ISSN (Online): 1939-327X
• Published Online: 22 September 2016
• Copyright Holders: Copyright © 2016 American Diabetes Association
• First Published: First published in Diabetes 65(10): 3091-3103
• Publisher Policy: Reproduced in accordance with the publisher copyright policy

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