Effects of serum bilirubin on atherosclerotic processes

Figures & data

Figure 1. The enzyme heme oxygenase catalyses the breakdown of heme to the products biliverdin, carbon dioxide, and iron. Biliverdin reductase converts biliverdin to bilirubin. NADP = nicotinamide adenine dinucleotide phosphate; NADPH = reduced form of NADP; CO = carbon dioxide; Fe²⁺ = iron(II).

Table I. Evidences for the protective role of bilirubin against atherosclerosis.

Related process	Type	Outcomes	Ref.
Study characteristics
Antioxidant	In vitro	Bilirubin, at micromolar concentrations, efficiently scavenges peroxyl radicals generated chemically. In liposomes, bilirubin suppresses the oxidation more than does α-tocopherol	10
	In vitro	Depletion of bilirubin by RNA interference markedly augments tissue levels of reactive oxygen species and causes apoptotic cell decrease. Antioxidant capacity was greater than that of glutathione	11
	In vitro	UCB, at the normal serum level, inhibits oxidation of LDL cholesterol. UCB is more than 20 times more effective than trolox in preventing LDL oxidation.	43
	In vivo, animal	Mice with depletion of HO-2 display greater lipid than protein oxidation. RNA interference depletion of BVR increases oxidation of lipids more than protein.	44
	In vivo, animal	Serum bilirubin protects against serum oxidative damage in the first days of life in neonatal Gunn rats exposed to hyperoxia. Serum lipid hydroperoxides in jaundiced rats was lower than that in non-jaundiced rats	45
	In vivo, human	Increases in the concentration of uric acid, bilirubin, and ascorbic acids after aerobic exercise result in a significant increase in total antioxidant serum capacity	46
Inflammation	In vitro	HO-1 induction or pretreatment with bilirubin resulted in the reduction of monocyte chemotaxis in response to LDL oxidation	47
	In vitro	Enhanced HO activity with the increase of bilirubin suppresses not only Ag II-stimulated superoxide formation, but also Ag II-enhanced chemotactic activity	48
	In vivo, animal	Bilirubin blocks VCAM-1-dependent lymphocyte migration in vitro and ameliorates VCAM-1-mediated airway inflammation in vivo in a murine asthma model	49
	In vivo, animal	Induction of HO-1 in endothelial cells and foam cells and accumulation of bilirubin in foam cells were observed in atherosclerotic lesions of hypercholesterolemic rabbits	50
	In vivo, animal	Induction of HO-1 or superfusion with bilirubin at the micromolar level decreases rolling and adherent responses of leukocytes in venule which is provoked by oxidative stress and ischaemia-reperfusion in rats	51
	In vivo, animal	Induction of HO-1 or bilirubin treatment attenuated proinflammatory responses and improved impaired endothelium-dependent vascular relaxation response in thoracic aorta from high-fat-fed LDL receptor knock-out mice	52
	In vitro	UCB attenuates overexpression of adhesion molecules via inhibition of the NF-kB transduction pathway	53
	In vitro	UCB limits the overexpression of adhesion molecules and inhibits the PMN endothelial adhesion induced by the TNF-α in endothelial cell lines	14
Smooth muscle cell proliferation	In vivo, animal	Bilirubin inhibited VSMC cycle progression at the G1 phase and prevented intimal hyperplasia after balloon injury in hyperbilirubinemic Gunn rats	54
	In vivo, animal	Bilirubin reduced phosphorylation of p38 MAPK and JNK1/2 in VSMC and inhibited vascular stenosis after balloon injury in hyperbilirubinemic Gunn rats	55
	In vivo, animal	Local administration of bilirubin immediately following balloon injury of rat carotid arteries attenuated neointimal formation. Bilirubin significantly decreases in ERK activity in injured blood vessels	56
	In vitro	Bilirubin inhibits growth of proliferating human coronary artery smooth muscle cells and causes the transition from proliferative to contractile phenotype	57
	In vivo, human	Total bilirubin levels were negatively associated with ISR in 1076 patients who underwent coronary stenting and follow-up angiography	58
Endothelial dysfunction	In vivo, animal	Induction of HO-1 or administration of biliverdin can prevent endothelial cell sloughing in diabetic rats	59
	In vitro	Administration bilirubin attenuated mitochondrial dysfunction, caspase-3 activation, and cell death caused by the knockdown of HO-1 in human endothelial cells	60
	In vivo, human	Log-transformed total bilirubin is positively correlated with the change in coronary artery diameter to intra-coronary papaverine administration, which reflects the endothelial function in overweight patients who underwent coronary flow studies	18

Ag = angiotensin; BVR = biliverdin reductase; ERK = extracellular signal-regulated kinases; HO = heme oxygenase; ISR = in-stent restenosis; JNK = c-Jun N-terminal kinases; LDL = low-density lipoprotein; MAPK = mitogen-activated protein kinases; NF-kB = nuclear factor-kappa B; PMN = polymorphonuclear leukocytes; TNF-α = tumour necrosis factor-α; UCB = unconjugated bilirubin; VCAM-1 = vascular cell adhesion molecule 1; VSMC = vascular smooth muscle cells.

Figure 2. Protective role of bilirubin against atherosclerosis. Oxidation of LDL and ROS itself involves atherosclerosis progression. Bilirubin has antioxidant properties, inhibits monocyte chemotaxis, attenuates expression of adhesion molecules on endothelial cells, improves endothelial dysfunction, and inhibits proliferation of VSMCs. Protective properties of bilirubin in the atherosclerotic processes are indicated as blue dotted arrows. LDL = low-density lipoprotein; MCP-1 = monocyte chemotactic protein-1; ROS = reactive oxygen species; VSMC = vascular smooth muscle cell.