The role of biliverdin reductase A in cardiovascular and metabolic diseases.

Abstract

Epidemiological studies show plasma concentrations of bilirubin, formed by biliverdin reductase A (BVRA), to inversely associate with the risk of cardiovascular and metabolic diseases. However, a causative link between bilirubin and these diseases remains to be established. Global Bvra gene knockout (Bvra-/-) mice were generated to assess the role of bilirubin in cardiometabolic diseases. Bvra-/- mice were healthy and fecund, had ~100-fold lower plasma bilirubin, ~25-fold higher plasma biliverdin and phenotypic green-coloured bile compared with their wild-type counterpart. BVRA deficiency had no measurable effect on plasma lipids and antioxidants. However, Bvra-/- mice had higher concentrations of plasma lipid hydroperoxides and their erythrocyte peroxiredoxin 2 was more oxidized, indicative of the presence of systemic oxidative stress. To assess the role of bilirubin in cardiovascular disease, Bvra-/- mice were crossed with hyperlipidemic apolipoprotein-E gene knockout (Apoe-/-) mice and subjected to tandem stenosis (TS) of the right carotid artery, a model of plaque instability. Compared with Bvra+/+Apoe-/-, Bvra-/-Apoe-/- TS mice lacked bilirubin, were hyperlipidemic and had enhanced endothelial dysfunction and atherosclerosis. Unstable plaque in Bvra-/-Apoe-/- TS mice had increased positive remodeling and decreased fibrous cap thickness compared with unstable plaque in Bvra+/+Apoe-/- TS mice that contained BVRA activity, indicating that BVRA/bilirubin attenuates atherogenesis and plaque destabilization. BVRA has been proposed to regulate insulin signaling and lipid metabolism. Contrary to this, Bvra+/+ and Bvra-/- mice fed high fat diet had similar plasma lipids, glucose, and insulin signaling and tolerance. However, BVRA deficiency in combination with a high fat diet increased hepatic concentrations of cholesterol and triglycerides, indicating that BVRA/bilirubin deficiency enhances hepatic steatosis, but not insulin resistance. Overall, our data show that while Bvra is not an essential gene, its absence increases systemic oxidative stress in naïve mice. In combination with a fat-rich diet, the absence of BVRA and bilirubin causes a pro-atherogenic phenotype, characterized by increased hyperlipidemia, endothelial dysfunction and atherogenesis, as well as plaque destabilization, compensatory arterial remodeling and hepatic steatosis. This phenotype is consistent with bilirubin decreasing cardiovascular and metabolic diseases.