Unconjugated bilirubin exerts pro-apoptotic effect on platelets via p38-MAPK activation

NaveenKumar, Somanathapura K. ; Thushara, Ram M. ; Sundaram, Mahalingam S. ; Hemshekhar, Mahadevappa ; Paul, Manoj ; Thirunavukkarasu, Chinnasamy ; Basappa, . ; Nagaraju, Ganesh ; Raghavan, Sathees C. ; Girish, Kesturu S. ; Kemparaju, Kempaiah ; Rangappa, Kanchugarakoppal S. (2015) Unconjugated bilirubin exerts pro-apoptotic effect on platelets via p38-MAPK activation Scientific Reports, 5 . Article ID 15045, 16 pages. ISSN 2045-2322


Official URL: http://www.nature.com/articles/srep15045

Related URL: http://dx.doi.org/10.1038/srep15045


Thrombocytopenia is one of the most frequently observed secondary complications in many pathological conditions including liver diseases, where hyperbilirubinemia is very common. The present study sought to find the cause of thrombocytopenia in unconjugated hyperbilirubinemic conditions. Unconjugated Bilirubin (UCB), an end-product of heme catabolism, is known to have pro-oxidative and cytotoxic effects at high serum concentration. We investigated the molecular mechanism underlying the pro-apoptotic effect of UCB on human platelets in vitro and followed it up with studies in phenylhydrazine-induced hyperbilirubinemic rat model and hyperbilirubinemic human subjects. UCB is indeed found to significantly induce platelet apoptotic events including elevated endogenous reactive oxygen species generation, mitochondrial membrane depolarization, increased intracellular calcium levels, cardiolipin peroxidation and phosphatidylserine externalization (p < 0.001) as evident by FACS analysis. The immunoblots show the elevated levels of cytosolic cytochrome c and caspase activation in UCB-treated platelets. Further, UCB is found to induce mitochondrial ROS generation leading to p38 activation, followed by downstream activation of p53, ultimately resulting in altered expression of Bcl-2 and Bax proteins as evident from immunoblotting. All these parameters conclude that elevated unconjugated bilirubin causes thrombocytopenia by stimulating platelet apoptosis via mitochondrial ROS-induced p38 and p53 activation.

Item Type:Article
Source:Copyright of this article belongs to Nature Publishing Group.
ID Code:104164
Deposited On:07 Apr 2017 06:25
Last Modified:07 Apr 2017 06:25

Repository Staff Only: item control page