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MK2206 attenuates atherosclerosis by inhibiting lipid accumulation, cell migration, proliferation, and inflammation

Abstract

Cardiovascular disease is a common comorbidity in patients with cancer, and the main leading cause of noncancer-related deaths in cancer survivors. Considering that current antitumor drugs usually induce cardiovascular injury, the quest for developing new antitumor drugs, especially those with cardiovascular protection, is crucial for improving cancer prognosis. MK2206 is a phase II clinical anticancer drug and the role of this drug in cardiovascular disease is still unclear. Here, we revealed that MK2206 significantly reduced vascular inflammation, atherosclerotic lesions, and inhibited proliferation of vascular smooth muscle cell in ApoE−/− mice in vivo. We demonstrated that MK2206 reduced lipid accumulation by promoting cholesterol efflux but did not affect lipid uptake and decreased inflammatory response by modulating inflammation-related mRNA stability in macrophages. In addition, we revealed that MK2206 suppressed migration, proliferation, and inflammation in vascular smooth muscle cells. Moreover, MK2206 inhibited proliferation and inflammation of endothelial cells. The present results suggest that MK2206, as a promising drug in clinical antitumor therapy, exhibits anti-inflammatory and antiatherosclerotic potential. This report provides a novel strategy for the prevention of cardiovascular comorbidities in cancer survivors.

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Fig. 1: MK2206 attenuated atherosclerosis in ApoE−/− mice.
Fig. 2: Cell viability assay and Akt activity in response to MK2206.
Fig. 3: MK2206 inhibited macrophage-derived foam cell formation.
Fig. 4: MK2206 inhibited inflammation in macrophages.
Fig. 5: MK2206 inhibited migration, proliferation, and inflammation in VSMCs.
Fig. 6: MK2206 reduced the inflammatory response in HUVECs.

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Acknowledgements

This study was financially supported by the National Key Research and Development Program of China Grants 2019YFA0801700 and 2019YFA0801800 (to JW), National Natural Science Foundation of China Grants 81800359 (to HMZ), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-1-006) (to JW), Peking Union Medical College Youth Fund/Fundamental Research Funds for the Central University (3332016048) (to HMZ), National Key Research and Development program of China, Ministry of Science and Technology of China (2018YFC1315100) to (HMZ), and National Natural Science Foundation of China Grants 81622008 and 81470579 (to JW).

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JW and HMZ designed and supervised the research. YQT performed the experiments, analyzed the data, and wrote the paper. HMZ and CG performed some of the experiments. ZWL, CLH, HQY, and YFF contributed to the writing of the paper. PRY, HMZ, and JW contributed to the critical revision of the manuscript. All authors provided final approval of the article.

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Correspondence to Hong-mei Zhao or Jing Wang.

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Tang, Yq., Li, Zw., Feng, Yf. et al. MK2206 attenuates atherosclerosis by inhibiting lipid accumulation, cell migration, proliferation, and inflammation. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00729-x

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Keywords

  • atherosclerosis
  • Akt
  • MK2206
  • inflammation
  • cholesterol efflux

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