Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Abstract

We have recently shown that the natural bile pigment bilirubin has antiproliferative effects on vascular smooth muscle cells (VSMCs). Bilirubin is the end product of heme catabolism mediated by heme oxygenases and has for decades been considered a toxic waste product of our bodies. However, 14 separate studies and a meta-analysis have documented an inverse correlation between atherosclerosis and the levels of bilirubin in normal individuals. Having high normal or supranormal levels of bilirubin is associated with less atherosclerotic-type disease as compared with that in individuals with low normal levels of bilirubin. This combined with experimental data showing anti-atherosclerotic properties of the enzyme heme oxygenase-1 encouraged us to hypothesize that bilirubin and its precursor biliverdin, would act to ameliorate components of atherosclerosis, in a manner similar to what has been shown with HO-1. Both did so in an animal model of restenosis in which vascular smooth muscle cell proliferation leads to intimal proliferation and causes narrowing of the vessels. We also analyzed the antiproliferative effects of the bile pigments in an in vitro system where bilirubin/biliverdin caused p53 dependent cell cycle arrest by hypophosphorylation of the retinoblastoma tumor suppressor protein in growth factor stimulated VSMCs.

Pharmacological and Clinical Aspects of Heme Oxygenase

“…Direct evidence for the role of CO in vascular response was presented when it was shown that a reduction in CO generation resulted in increased vascular resistance in rat liver (Suematsu et al, 1994). Subsequent studies have clearly shown that HO-1-derived CO and bilirubin result in a vasorelaxant effect not only via cGMP-dependent but also via cGMP-independent (Ollinger et al, 2007;Li et al, 2008) stimulation of certain K channels Wang et al, , 2001Dong et al, 2007) and an increase in adiponectin levels (L'Abbate et al., 2007). Furthermore, it is considered unlikely that CO and NO represent redundant messenger molecules, even though both are active in the vessel wall.…”

“…Wang and associates (Cannon, 1929;Wang andWu, 1997, 2003;Wang, 1998;Ollinger et al, 2007;Li et al, 2008) have presented a series of elegant papers showing that CO-mediated relaxation was partially blocked by inhibitors of BK Ca channels without affecting Ca homeostasis. Other investigators have shown that CO and CO-releasing molecule (CORM)-3 stimulate BK Ca channels in HEK-293 cells Xi et al, 2004).…”

Treatment of Obese Diabetic Mice With a Heme Oxygenase Inducer Reduces Visceral and Subcutaneous Adiposity, Increases Adiponectin Levels, and Improves Insulin Sensitivity and Glucose Tolerance

“…PPAR␥ agonists are shown to induce both HO-1 (21) and the rate-limiting chaperone protein EroL (46,47). PPAR␥ agonist that increases adiponectin may do so by increasing the levels of EroL chaperone protein (46).…”

“…PPAR␥ agonists are shown to induce both HO-1 (21) and the rate-limiting chaperone protein EroL (46,47). PPAR␥ agonist that increases adiponectin may do so by increasing the levels of EroL chaperone protein (46). Because PPAR␥ also increases HO-1 protein levels (21) and HO-1 is known as a chaperone protein, it is possible that one of the mechanisms by which HO-1 can increase adiponectin levels is through more efficient adiponectin stabilization and protection.…”

Az ösztrogénhiány, elhízás és a szabadidős testmozgás hatásának vizsgálata állatkísérletes modellekben

“…A CO és NO együttes vazorelaxáns hatása a sGC és cGMP útvonalakon keresztül érvényesül. A CO vazodilatív hatása a cGMP útvonalon kívül a kalcium-aktivált kálium csatornák (BKCa) aktiválásával is megvalósulhat [47,48]. Az antioxidáns és vazoaktív hatások mellett a HO-1-nek szerepe van az angiogenezisben és proliferációban is, valamint gyulladáscsökkentő és antiapoptotikus hatással is bír.…”