The Bilirubin-Increasing Drug Atazanavir Improves Endothelial Function in Patients With Type 2 Diabetes Mellitus

Dekker, D.; Dorresteijn, Mirrin J.; Pijnenburg, Margot; Heemskerk, Suzanne; Rasing-Hoogveld, A.; Burger, David M.; Wagener, Frank A. D. T. G.; Smits, Paul

doi:10.1161/atvbaha.110.211789

Cited by 102 publications

(104 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…35 Dekker et al 36 have shown that an increased level of bilirubin induced by atazanavir improves endothelium-dependent vasodilation in patients with type 2 diabetes mellitus, supporting our findings. However, in contrast, Dubé et al 37 found no change in endothelial function in healthy subjects treated with atazanavir despite an increase in bilirubin level.…”

Section: Discussionsupporting

confidence: 89%

Hyperbilirubinemia, Augmentation of Endothelial Function, and Decrease in Oxidative Stress in Gilbert Syndrome

et al. 2012

View full text Add to dashboard Cite

Background— Patients with Gilbert syndrome have mild unconjugated hyperbilirubinemia. It has been shown that bilirubin is an endogenous antioxidant. We evaluated the role of oxidative stress in endothelial function in patients with Gilbert syndrome under normal conditions without cardiovascular risk factors. Methods and Results— A total of 108 young men with Gilbert syndrome without cardiovascular risk factors and 108 age-matched healthy men (normal controls) were enrolled in this study. Serum concentrations of bilirubin were higher in patients with Gilbert syndrome than in control subjects (29.2±11.6 versus 9.4±2.7 μmol/L; P <0.001). Serum concentrations of malondialdehyde-modified low-density lipoprotein and urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG), as indices of oxidative stress, were lower in patients with Gilbert syndrome than in control subjects (61.8±24.5 versus 72.5±21.8 U/L, P =0.034; 7.8±2.4 versus 10.4±3.2 ng/mg creatinine, P =0.001, respectively). Flow-mediated vasodilation was greater in patients with Gilbert syndrome than in normal control subjects (7.2±2.2% versus 5.9±1.7%; P <0.001). Vascular responses to nitroglycerine were not significantly different between the 2 groups. Flow-mediated vasodilation correlated with serum concentration of bilirubin ( r =0.44, P <0.001), malondialdehyde-modified low-density lipoprotein ( r =−0.25, P =0.01), and urinary excretion of 8-OHdG ( r =−0.27, P =0.004) in patients with Gilbert syndrome but not in control subjects. In addition, serum concentration of bilirubin correlated with malondialdehyde-modified low-density lipoprotein ( r =−0.20, P =0.04) and 8-OHdG ( r =−0.21, P =0.02) in patients with Gilbert syndrome but not in control subjects. Conclusions— Patients with Gilbert syndrome had low levels of oxidative stress associated with hyperbilirubinemia and enhancement of endothelium-dependent vasodilation. Clinical Trial Registration— URL: http://www.umin.ac.jp . Unique identifier: UMIN000003409.

show abstract

Section: Discussionsupporting

confidence: 89%

Hyperbilirubinemia, Augmentation of Endothelial Function, and Decrease in Oxidative Stress in Gilbert Syndrome

et al. 2012

View full text Add to dashboard Cite

show abstract

“…HO-1 degrades heme to form biliverdin, CO, and Fe 2+ ; the former is further converted into unconjugated bilirubin. Bilirubin is increasingly recognized to be vasoprotective in cardiometabolic diseases (18,20), and the total plasma bilirubin concentration is lower in diabetic patients (17). The current study also shows a reduced serum level of unconjugated bilirubin in db/db mice, which is increased after 2 weeks of hemin treatment.…”

Section: Discussionsupporting

confidence: 62%

“…Bilirubin is a potent antioxidant, and efforts have been directed to determine whether bilirubin can be used to treat diseases associated with oxidative stress. Indeed, atazanavir, a drug that raises unconjugated bilirubin levels, enhances plasma antioxidant capacity and improves EDRs in diabetic patients (20).…”

mentioning

confidence: 99%

Unconjugated Bilirubin Mediates Heme Oxygenase-1–Induced Vascular Benefits in Diabetic Mice

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

“…Atazanavir has even been tested in HIV‐negative diabetic patients to determine its effect on carotid intimal thickness. In one of these trials, endothelial function improved,16 whereas the second study showed only a reduction in low‐density lipoprotein levels and blood pressure 17. To potentially explain these mixed findings, atazanavir and other protease inhibitors have been shown to actually increase endothelial dysfunction, oxidative stress, and von Willebrand factor, thereby counteracting some of the benefits of the elevated bilirubin levels 46, 47, 48.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the antiretroviral drug atazanavir can competitively inhibit uridine diphosphate glucuronosyltransferase 1A1, leading to an increase in unconjugated bilirubinemia 15. Several studies have shown atazanavir use can improve endothelial function and reduce lipid levels and blood pressure in HIV‐uninfected diabetic patients 16, 17. Among HIV‐positive individuals, atazanavir decreased markers of inflammation and slowed progression of carotid intimal‐medial thickness when compared with other antiretroviral treatment (ART), an effect that appears to be partially mediated by bilirubin 18, 19…”

mentioning

confidence: 99%

Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV‐Positive and HIV‐Negative Individuals in VACS (Veterans Aging Cohort Study)

Marconi

Duncan

So‐Armah

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundBilirubin may protect against cardiovascular disease (CVD) by reducing oxidative stress. Whether elevated bilirubin reduces the risk of CVD events among HIV + individuals and if this differs from uninfected individuals remain unclear. We assessed whether bilirubin independently predicted the risk of CVD events among HIV + and uninfected participants in VACS (Veterans Aging Cohort Study).Methods and ResultsWe conducted a prospective cohort study using VACS participants free of baseline CVD. Total bilirubin was categorized by quartiles. CVD as well as acute myocardial infarction, heart failure, and ischemic stroke events were assessed. Cox regression was used to evaluate hazard ratios of outcomes associated with quartiles of total bilirubin in HIV + and uninfected people after adjusting for multiple risk factors. There were 96 381 participants (30 427 HIV +); mean age was 48 years, 48% were black, and 97% were men. There were 6603 total incident CVD events over a mean of 5.7 years. In adjusted models, increasing quartiles of baseline total bilirubin were associated with decreased hazards of all outcomes (hazard ratio, 0.86; 95% confidence interval, 0.80–0.91). Among HIV + participants, results persisted for heart failure, ischemic stroke, and total CVD, but nonsignificant associations were observed for acute myocardial infarction.Conclusions VACS participants (regardless of HIV status) with elevated bilirubin levels had a lower risk of incident total CVD, acute myocardial infarction, heart failure, and ischemic stroke events after adjusting for known risk factors. Future studies should investigate how this apparently protective effect of elevated bilirubin could be harnessed to reduce CVD risk or improve risk estimation among HIV + individuals.

show abstract

The Bilirubin-Increasing Drug Atazanavir Improves Endothelial Function in Patients With Type 2 Diabetes Mellitus

Cited by 102 publications

References 41 publications

Hyperbilirubinemia, Augmentation of Endothelial Function, and Decrease in Oxidative Stress in Gilbert Syndrome

Hyperbilirubinemia, Augmentation of Endothelial Function, and Decrease in Oxidative Stress in Gilbert Syndrome

Unconjugated Bilirubin Mediates Heme Oxygenase-1–Induced Vascular Benefits in Diabetic Mice

Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV‐Positive and HIV‐Negative Individuals in VACS (Veterans Aging Cohort Study)

Contact Info

Product

Resources

About