Beyond a Measure of Liver Function—Bilirubin Acts as a Potential Cardiovascular Protector in Chronic Kidney Disease Patients
by Ming-Tsun Tsai 1,2OrcID and Der-Cherng Tarng 1,2,3,*OrcID
Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
Institute of Clinical Medicine, National Yang-Ming University, Taipei 11217, Taiwan
Department and Institute of Physiology, National Yang-Ming University, Taipei 11217, Taiwan
Received: 28 November 2018 / Accepted: 21 December 2018 / Published: 29 December 2018
Abstract: Bilirubin is a well-known neurotoxin in newborn infants; however, current evidence has shown that a higher serum bilirubin concentration in physiological ranges is associated with a lower risk for the development and progression of both chronic kidney disease (CKD) and cardiovascular disease (CVD) in adults. The protective mechanisms of bilirubin in CVD, CKD, and associated mortality may be ascribed to its antioxidant and anti-inflammatory properties. Bilirubin further improves insulin sensitivity, reduces low-density lipoprotein cholesterol levels and inhibits platelet activation in at-risk individuals. These effects are expected to maintain normal vascular homeostasis and thus reduce the incidence of CKD and the risks of cardiovascular complications and death. In this review, we highlight the recent advances in the biological actions of bilirubin in the pathogenesis of CVD and CKD progression, and further propose that targeting bilirubin metabolism could be a potential approach to ameliorate morbidity and mortality in CKD patients.
Bilirubin and Maintenance of Vascular Integrity
The vascular endothelium is a highly differentiated cellular monolayer that forms an active barrier between the bloodstream and the underlying tissues. The endothelial cells exert a remarkable impact on vascular homeostasis via the balance between a variety of relaxing and contractile factors in response to physiological and pathological stimuli. Endothelial dysfunction in patients with CKD may result from several conditions including hypertension or dyslipidemia, as well as nontraditional risk factors such as free radicals and inflammation . Dysfunction of the systemic vascular endothelium can lead to vascular remodeling, and consequently the development and progression of CVD. Moreover, renal endothelial injury and microvascular dysfunction also play a critical role in renal fibrosis and progression of CKD through parenchymal hypoxia, local inflammation, and the process of endothelial-to-mesenchymal transition (EndMT) [71,72]. Therefore, the endothelium may represent an important therapeutic target in CKD.
Several studies have demonstrated the benefits of elevated bilirubin concentrations in the maintenance of endothelial homeostasis in general populations and patients at high risk for vascular events. Gullu et al. investigated the relationship between serum bilirubin levels and coronary endothelial function in young adults without cardiovascular risk factors . They found that elevated bilirubin concentrations are associated with preserved coronary flow reserve and decreased levels of hsCRP. Elevated serum bilirubin levels were also found to be associated with decreased carotid intima-media thickness and lower plaque burden in patients with familial and nonfamilial dyslipidemia . These data indicate that bilirubin can protect against coronary microvascular dysfunction and progression of atherosclerosis by reducing inflammation and improving endothelium-dependent vasodilation.
As stated before, oxidative stress is well-known for its involvement in the pathogenesis of the endothelial dysfunction and atherosclerosis . In 2012, Maruhashi et al. first reported that high levels of bilirubin are associated with a significant reduction in oxidative stress biomarkers and enhanced endothelium-dependent flow-mediated vasodilation in people with Gilbert’s syndrome . Furthermore, a recent study has found that physiological concentrations of bilirubin could dose-dependently inhibit VCAM-1- and ICAM-1-mediated migration of monocytes across activated human endothelial cells by scavenging intracellular ROS . These findings were validated in a murine model of atherosclerosis, in which it was shown that administration of bilirubin significantly prevented atherosclerotic plaque formation and reduced inflammatory cell infiltration in aortic root lesions . Thus, the potent antioxidant effects of bilirubin may offer a significant protection against endothelial dysfunction and atherosclerosis in patients at risk of CVD.
Bilirubin also has a profound impact on nitric oxide (NO) homeostasis in endothelial cells . NO is the most important endothelium-derived relaxing substance, which plays a critical role in the protection against the onset and progression of CVD in patients with kidney disease. The bioactivity of endothelium-derived NO is reduced by superoxide, a major ROS. The excessive production of superoxide can react with NO to form the powerful oxidant peroxynitrite (ONOO−), which may induce extensive oxidative DNA and protein damage . Decreased intracellular superoxide level under conditions of hyperbilirubinemia is therefore expected to reduce ONOO− formation and increase the local NO bioavailability . In addition, bilirubin can preserve local concentrations of NO via direct scavenging activity of ONOO− .
Endothelial dysfunction in response to inflammatory processes and oxidative stress could induce vascular smooth muscle cell (VSMC) migration and proliferation . Aberrant proliferation and migration of VSMC to the intima have been closely linked to the development and progression of atherosclerotic CVD . Ollinger et al. firstly revealed that neointima formation was significantly reduced following carotid artery balloon injury in Gunn rats than in controls . Using the same experimental model of vascular damage, Peyton et al. also found that local perivascular administration of bilirubin could attenuate neointima hyperplasia in wild-type rats . These authors further reported that bilirubin exerted a dose-dependent anti-proliferative activity on VSMCs in vitro . Bilirubin induced cell cycle arrest in the G0/G1 phase, which was mediated through inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway and reduced phosphorylation of retinoblastoma protein . Moreover, bilirubin also induces Ca2+ influx and calpain II activation that leads to increased proteolytic cleavage of YY1, an important transcription factor that regulates cell cycle progression in VSMCs .
Endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis after vascular injury . Altered function and decreased number of circulating EPCs in patients with CKD have been well established and are recognized as key factors involved in the pathogenesis of endothelial dysfunction and CV complications . A recent study by Jabarpour et al. found that circulating EPCs from infants with hyperbilirubinemia exhibited greater proliferative and migratory capacity as compared with EPCs from those with normal bilirubin levels . Additionally, conditioned medium from EPCs isolated from hyperbilirubinemic infants could significantly increase levels of VEGF, IL-10, and p-ERK/ERK in the wound tissues and improve wound healing in the experimental animals . Using in vitro functional assays and an in vivo murine hind-limb ischemia model, Ikeda et al. further demonstrated that bilirubin may directly promote angiogenesis through activation of Akt/eNOS signaling in endothelial cells .
The abovementioned studies extend the understanding of the role of bilirubin in the regulation of endothelial integrity; however, it remains to be validated whether elevated serum bilirubin levels, within the physiological range, can improve endothelial function and thus reduce cardiovascular morbidity and mortality in individuals with CKD.
Keywords: antioxidant; bilirubin; cardiovascular disease; chronic kidney disease; oxidative stress
IJMS | Free Full-Text | Beyond a Measure of Liver Function—Bilirubin Acts as
a Potential Cardiovascular Protector in Chronic Kidney Disease Patients | HTML