High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor Class B Type i

Joanne T.M. Tan, Hamish C.G. Prosser, Louise L. Dunn, Laura Z. Vanags, Anisyah Ridiandries, Tania Tsatralis, Laura Leece, Zoë E. Clayton, Sui Ching G. Yuen, Stacy Robertson, Yuen Ting Lam, David S. Celermajer, Martin K.C. Ng, Christina A. Bursill

Research output: Contribution to journalArticleResearchpeer-review

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 keymediators 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-1a 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.

Original languageEnglish
Pages (from-to)3091-3103
Number of pages13
JournalDiabetes
Volume65
Issue number10
DOIs
Publication statusPublished - Oct 2016
Externally publishedYes

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Class B Scavenger Receptors
HDL Lipoproteins
CD36 Antigens
Diabetic Angiopathies
Small Interfering RNA
Ischemia
Prolyl Hydroxylases
Hypoxia-Inducible Factor 1
Vascular Endothelial Growth Factor Receptor-2
1-Phosphatidylinositol 4-Kinase
Nitric Oxide Synthase Type III
Wounds and Injuries
Hindlimb
Streptozocin
Hypoglycemic Agents
Wound Healing
Vascular Endothelial Growth Factor A
Blood Vessels
Phosphorylation
Glucose

Cite this

Tan, J. T. M., Prosser, H. C. G., Dunn, L. L., Vanags, L. Z., Ridiandries, A., Tsatralis, T., ... Bursill, C. A. (2016). High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor Class B Type i. Diabetes, 65(10), 3091-3103. https://doi.org/10.2337/db15-1668
Tan, Joanne T.M. ; Prosser, Hamish C.G. ; Dunn, Louise L. ; Vanags, Laura Z. ; Ridiandries, Anisyah ; Tsatralis, Tania ; Leece, Laura ; Clayton, Zoë E. ; Yuen, Sui Ching G. ; Robertson, Stacy ; Ting Lam, Yuen ; Celermajer, David S. ; Ng, Martin K.C. ; Bursill, Christina A. / High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor Class B Type i. In: Diabetes. 2016 ; Vol. 65, No. 10. pp. 3091-3103.
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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 keymediators 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-1a 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.",
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Tan, JTM, Prosser, HCG, Dunn, LL, Vanags, LZ, Ridiandries, A, Tsatralis, T, Leece, L, Clayton, ZE, Yuen, SCG, Robertson, S, Ting Lam, Y, Celermajer, DS, Ng, MKC & Bursill, CA 2016, 'High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor Class B Type i', Diabetes, vol. 65, no. 10, pp. 3091-3103. https://doi.org/10.2337/db15-1668

High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor Class B Type i. / Tan, Joanne T.M.; Prosser, Hamish C.G.; Dunn, Louise L.; Vanags, Laura Z.; Ridiandries, Anisyah; Tsatralis, Tania; Leece, Laura; Clayton, Zoë E.; Yuen, Sui Ching G.; Robertson, Stacy; Ting Lam, Yuen; Celermajer, David S.; Ng, Martin K.C.; Bursill, Christina A.

In: Diabetes, Vol. 65, No. 10, 10.2016, p. 3091-3103.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Dunn, Louise L.

AU - Vanags, Laura Z.

AU - Ridiandries, Anisyah

AU - Tsatralis, Tania

AU - Leece, Laura

AU - Clayton, Zoë E.

AU - Yuen, Sui Ching G.

AU - Robertson, Stacy

AU - Ting Lam, Yuen

AU - Celermajer, David S.

AU - Ng, Martin K.C.

AU - Bursill, Christina A.

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N2 - 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 keymediators 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-1a 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.

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Tan JTM, Prosser HCG, Dunn LL, Vanags LZ, Ridiandries A, Tsatralis T et al. High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor Class B Type i. Diabetes. 2016 Oct;65(10):3091-3103. https://doi.org/10.2337/db15-1668