Nitric oxide promotes caspase-independent hepatic stellate cell apoptosis through the generation of reactive oxygen species

Daniel A. Langer, Amitava Das, David Semela, Ningling Kang-Decker, Helen Hendrickson, Steven F. Bronk, Zvonimir S. Katusic, Gregory J. Gores, Vijay H. Shah

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


Hepatic stellate cells (HSCs) contribute to portal hypertension through multiple mechanisms that include collagen deposition, vasoconstriction, and regulation of sinusoidal structure. Under normal physiologic conditions, endothelial nitric oxide (NO) synthase-derived NO exerts paracrine effects on HSCs; however, in cirrhosis, NO generation is impaired in association with concomitant HSC activation and changes in sinusoidal structure, events that contribute significantly to the development of portal hypertension. These concepts, in combination with recent evidence that induction of HSC-selective apoptosis may represent a useful target for treatment of chronic liver disease, led us to examine if NO may further limit HSC function through apoptosis. Indeed, both NO donors and endothelial NO synthase overexpression promoted HSC apoptotic pathways. HSC death conferred by NO occurred through mitochondrial membrane depolarization and through a caspase-independent pathway. Furthermore, NO-induced apoptosis of HSC did not occur through the canonical pathways of soluble guanylate cyclase or protein nitration, but rather through the generation of superoxide and hydroxyl radical intermediates. Lasdy, HSC isolated from rats after bile duct ligation were more susceptible to NO-induced apoptosis. These data indicate that NO promotes HSC apoptosis through a signaling mechanism that involves mitochondria, is mediated by reactive oxygen species, and occurs independent of caspase activation. Conclusion: We postulate that NO-dependent apoptosis of HSCs may maintain sinusoidal homeostasis, and may represent an additional beneficial effect of NO donors for therapy of portal hypertension.

Original languageEnglish (US)
Pages (from-to)1983-1993
Number of pages11
Issue number6
StatePublished - Jun 2008

ASJC Scopus subject areas

  • Hepatology


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