Am J Cardiovasc Dis 2013;3(3):135-145

Original Article
Gambogic acid moderates cardiac responses to chronic hypoxia likely by
acting on the proteasome and NF-κB pathway

Canguo Zhao, Shouting Liu, Changshan Yang, Xiaofen Li, Hongbiao Huang, Ningning Liu, Shujue Li, Xuejun Wang, Jinbao

Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong
510182, China; The Cardiovascular Institute, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou,
Guangdong 510260, China; Guangdong Provincial Key Lab of Urology, Department of Urology, Minimally Invasive Surgery
Center, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510230, China; Division of
Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota 57069,
USA. Canguo Zhao and Shouting Liu contributed equally to this work.

Received July 12, 2013; Accepted July 27, 2013; Epub August 16, 2013; Published August 30, 2013

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. (AJCD1307003).

Keywords: Gambogic acid, chronic hypoxia, right ventricular hypertrophy, NF-κB

Address correspondence to: Dr. Jinbao Liu, Protein modification and Degradation Lab, Department of Pathophysiology,
Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R.C. Tel: +8620-81340720; Fax: +8620-81340542; E-
mail: or Dr. Xuejun Wang, Division of Basic Biomedical Science, Sanford School of Medicine,
University of South Dakota, Vermillion, SD 57069, USA. E-mail:
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