Unconjugated bilirubin mediates heme oxygenase-1-induced vascular benefits in diabetic mice

Jian Liu, Li Wang, Xiao Yu Tian, Limei Liu, Wing Tak Wong, Yang Zhang, Simon Q B HAN, Hing Man Ho, Nanping Wang, Siu Ling Wong, Zhen Yu Chen, Jun Yu, Chi Fai Ng, Xiaoqiang Yao, Yu Huang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

49 Citations (Scopus)


Heme oxygenase-1 (HO-1) exerts vasoprotective effects. Such benefit in diabetic vasculopathy, however, remains unclear. We hypothesize that bilirubin mediates HO-1-induced vascular benefits in diabetes. Diabetic db/db mice were treated with hemin (HO-1 inducer) for 2 weeks, and aortas were isolated for functional and molecular assays. Nitric oxide (NO) production was measured in cultured endothelial cells. Hemin treatment augmented endothelium-dependent relaxations (EDRs) and elevated Akt and endothelial NO synthase (eNOS) phosphorylation in db/db mouse aortas, which were reversed by the HO-1 inhibitor SnMP or HO-1 silencing virus. Hemin treatment increased serum bilirubin, and ex vivo bilirubin treatment improved relaxations in diabetic mouse aortas, which was reversed by the Akt inhibitor. Biliverdin reductase silencing virus attenuated the effect of hemin. Chronic bilirubin treatment improved EDRs in db/db mouse aortas. Hemin and bilirubin reversed high glucose-induced reductions in Akt and eNOS phosphorylation and NO production. The effect of hemin but not bilirubin was inhibited by biliverdin reductase silencing virus. Furthermore, bilirubin augmented EDRs in renal arteries from diabetic patients. In summary, HO-1-induced restoration of endothelial function in diabetic mice is most likely mediated by bilirubin, which preserves NO bioavailability through the Akt/eNOS/NO cascade, suggesting bilirubin as a potential therapeutic target for clinical intervention of diabetic vasculopathy.

Original languageEnglish
Pages (from-to)1564-1575
Number of pages12
Issue number5
Publication statusPublished - May 2015

Scopus Subject Areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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