Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice

Abstract

-Population studies indicate that moderate hyperbilirubinemia is associated with reduced incidence of cardiovascular diseases, including hypertension. Despite this correlative evidence, no studies have directly tested the hypothesis that moderate increases in plasma bilirubin levels can attenuate the development of hypertension. This hypothesis was tested by treating mice with Indinavir, a drug that competes with bilirubin for metabolism by UDP-glucuronosyltransferase 1A1 (UGT1A1). Treatment of mice with Indinavir (500 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , gavage) resulted in a twofold increase in plasma unconjugated bilirubin levels. Next, we determined the effect of Indinavir-induced changes in plasma bilirubin on the development of ANG II-dependent hypertension. Moderate hyperbilirubinemia was induced 3 days before the implantation of an osmotic minipump that delivered ANG II at a rate of 1 g ⅐ kg Ϫ1 ⅐ min Ϫ1 . ANG II infusion increased mean arterial pressure (MAP) by 20 mmHg in control mice but by only 6 mmHg in mice treated with Indinavir (n ϭ 6). Similar to Indinavir treatment, direct infusion of bilirubin (37.2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 iv) resulted in a twofold increase in plasma bilirubin levels and also attenuated the development of ANG II-dependent hypertension. Moderate hyperbilirubinemia resulted in an increase in plasma nitrate/nitrite levels, which averaged 36 Ϯ 2 vs. 50 Ϯ 7 M in ANG II vehicle vs. Indinavir-treated mice (n ϭ 5). Moderate hyperbilirubinemia resulted in attenuation of vascular oxidative stress as determined by dihydroethidium staining of aortic segments. These results indicate that moderate hyperbilirubinemia prevents ANG IIdependent hypertension by a mechanism that may involve decreases in vascular oxidative stress. bilirubin; angiotensin II hypertension; uridine 5Ј-triphosphate-glucuronosyltransferase 1A1, heme oxygenase BILIRUBIN IS ONE of the by-products of heme catabolism by heme oxygenase (HO). Bilirubin is initially produced as biliverdin, which is rapidly converted by biliverdin reductase (BVR). HO and BVR are ubiquitous enzymes that render all mammalian cell types capable of producing bilirubin; however, the majority of circulating bilirubin is derived from the breakdown of hemoglobin by the reticuloendothelial system. The resultant bilirubin circulates bound to albumin to the liver where its entry into hepatocytes is mediated by the organic anion transporting polypeptide 2 (OATP2). Once in the hepatocyte, bilirubin is glucoronidated by UDP-glucuronyltransferase 1A1 (UGT1A1) and subsequently eliminated in the bile ducts through the multidrug resistance protein 2. The conjugated bilirubin is excreted via the common bile duct in the intestines as one of the components of bile salts.Recent population studies have revealed that elevated plasma bilirubin levels are associated with reduced incidence of cardiovascular diseases, including hypertension, coronary artery disease, atherosclerosis, and preeclampsia (5,6,17,19). More recent data from a study of Framingham offspring revealed that individuals ...

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

“…Nevertheless, UGT1A1 inhibition and parenteral administration of bilirubin comparably attenuated oxidative stress and hypertension in an angiotensin II-dependent animal model. 33 In our opinion, this supports a causal and dominant role of bilirubin. A similar approach with parenteral administration of bilirubin in humans may provide a definite proof of its beneficial impact on cardiovascular disease.…”

Hyperbilirubinemia modulates myocardial function, aortic ejection, and ischemic stress resistance in the Gunn rat

“…3A) point to alterations in Ca 2ϩ homeostasis and energy state (26), consistent with influences of bilirubin on Ca 2ϩ levels/regulatory proteins (11) and mitochondrial respiration (17). Antioxidant actions of bilirubin are likely to confer benefit in I/R, whereas elevated NO levels with hyperbilirubinemia may additionally contribute (33). Ben-Amotz et al (3) speculated that antioxidant effects of bilirubin inhibit the peroxidase activity of cytochrome c, oxidation of lipids such as cardiolipin, and thereby apoptosis.…”

“…Bulmer et al (7) revealed that GS plasma is less susceptible to copper-induced lipid oxidation, providing the first mechanistic insights into the decreased risk of atherosclerosis development in this cohort. The antioxidant effects of bilirubin may also improve vascular compliance via the prevention of vascular smooth muscle proliferation (24), increased nitric oxide (NO) production (19), and/or inhibition of NADPH activity/oxidative stress (29,33). However, despite current evidence indicating an "antiatherogenic" role for bilirubin, the discrete effects of endogenous bilirubin on cardiac function and ischemic tolerance have not been reported.…”

Bilirubin exerts pro-angiogenic property through Akt-eNOS-dependent pathway

“…30,31 Hyperbilirubinemia suppresses angiotensin II-induced hypertension through ameliorating endothelium-dependent vasodilation via the reduction of vascular oxidative stress in Gunn rats 32 or mice treated with a drug that competes with bilirubin. 33 Clinically, the oxidative stress is lower in patients with Gilbert's syndrome. 12 Moreover, Dekker et al 34 have clarified that a bilirubin-increasing drug ameliorated plasma antioxidant capacity in patients with type 2 diabetes mellitus.…”