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Author Notes:

Zhiyong Lin, zhiyong.lin@emory.edu

Nianguo Dong, dongnianguo@hust.edu.cn

Xianming Zhou: Conceptualization, Data curation, Validation, Investigation, Writing—review and editing. Chao Zhang: Conceptualization, Data curation, Funding acquisition, Investigation. Fei Xie: Data curation. Wei Wei: Data curation. Rui Li: Data curation. Qian Xu: Data curation. Yu Wang: Data curation. Philip A. Klenotic: Writing—review and editing. Goutham Narla: Conceptualization, Methodology, Writing—review and editing. Nianguo Dong: Supervision, Writing—review and editing. Zhiyong Lin: Conceptualization, Resources, Supervision, Funding acquisition, Writing—original draft, Project administration, Writing—review and editing.

The Icahn School of Medicine at Mount Sinai, on behalf of G. Narla, has filed patents covering composition of matter on the small molecules disclosed herein for the treatment of human cancer and other diseases (International Application Numbers: PCT/US15/19770, PCT/US15/19764; and US Patent: US 9,540,358 B2). RAPPTA Therapeutics LLC has licensed this intellectual property for the clinical and commercial development of this series of small molecule PP2A activators. G. Narla, has an ownership interest in RAPPTA Therapeutics LLC.


Research Funding:

NIH [grant numbers HL117759 (to Z.L.) and HL144741 (to Z.L. and G.N.)] and the National Natural Science Foundation of China [grant number 81600345 (to C.Z.)].


  • aortic aneurysm
  • protein phosphatase 2A

Allosteric activation of PP2A inhibits experimental abdominal aortic aneurysm.

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Journal Title:



Volume 135, Number 17


, Pages 2085-2097

Type of Work:

Article | Post-print: After Peer Review


Although extremely important, the molecular mechanisms that govern aortic aneurysm (AA) formation and progression are still poorly understood. This deficit represents a critical road-block toward the development of effective pharmaceutical therapies for the treatment of AA. While dysregulation of protein phosphatase 2A (PP2A) is thought to play a role in cardiovascular disease, its role in aortic aneurysm is unknown. The objective of the present study is to test the hypothesis that PP2A regulates abdominal aortic aneurysm (AAA) progression in a murine model. In an angiotensin II-induced AAA murine model, the PP2A inhibitor, LB-100, markedly accelerated AAA progression as demonstrated by increased abdominal aortic dilation and mortality. AAA progression was associated with elevated inflammation and extracellular matrix fragmentation, concomitant with increases in both metalloproteinase activity and reactive oxygen species production. Conversely, administration of a novel class of small molecule activators of PP2A (SMAPs) resulted in an antithetical effect. SMAPs effectively reduced AAA incidence along with the corresponding pathologies that were increased with LB-100 treatment. Mechanistically, modulation of PP2A activities in vivo functioned in part via alteration of the ERK1/2 and NFκB signaling pathways, known regulators of AAA progression. These studies, for the first time, demonstrate a role of PP2A in AAA etiology and demonstrate that PP2A activation may represent a novel strategy for the treatment of abdominal aortic aneurysms.
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