title: Gambogic acid moderates cardiac responses to chronic hypoxia likely by acting on the proteasome and NF-κB pathway.
abstract: Gambogic acid (GA) is the principal active ingredient of gamboges. GA was reported to exert anti-tumor and anti-inflammatory effects both in vitro and in vivo. Previously, we have shown that GA is a more tissue-specific proteasome inhibitor than bortezomib and it is less toxic to peripheral white blood cells compared to bortezomib. Ubiquitous proteasome inhibition was shown by some reports, but not by others, to prevent cardiac remodeling in response to pressure overload by blocking the NF-κB pathway; however, whether GA modulates the development of chronic hypoxia-induced right ventricular hypertrophy has not been investigated yet. Here we report that GA can significantly attenuate right ventricular hypertrophy induced by chronic hypoxia, reduce cardiac fibrosis, and remarkably block the reactivation of bona fide fetal genes in the cardiac tissue. Furthermore, we also investigated the potential molecular targets of GA on right ventricular hypertrophy. The results showed that GA could accumulate the IκB levels associated with decreased proteasomal activity, block the translocation of NF-κB from the cytoplasm to the nucleus, decrease NF-κB DNA-binding activity, and reduce IL-2 levels. In conclusion, GA is capable of preventing the development of chronic hypoxia-induced right ventricular hypertrophy. GA has great potential to be developed into an effective anti-hypertrophy agent.
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University Guangdong 510182, China.
authors.forename: Canguo
authors.initials: C
authors.lastname: Zhao
authors.forename: Shouting
authors.initials: S
authors.lastname: Liu
authors.forename: Changshan
authors.initials: C
authors.lastname: Yang
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.forename: Shujue
authors.initials: S
authors.lastname: Li
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
keywords: Gambogic acid; NF-κB; chronic hypoxia; right ventricular hypertrophy