Int J Biol Sci 2022; 18(13):5154-5167. doi:10.7150/ijbs.75577 This issue Cite

Research Paper

Role of PCK2 in the proliferation of vascular smooth muscle cells in neointimal hyperplasia

Dai Sik Ko1*, Junho Kang2*, Hye Jin Heo3, Eun Kyoung Kim3, Kihun Kim4, Jin Mo Kang1, YunJae Jung5,6,7, Seung Eun Baek3✉, Yun Hak Kim3,8✉

1. Division of Vascular Surgery, Department of General Surgery, Gachon University Gil Medical Center, Incheon, Republic of Korea.
2. Medical Research Institute, Pusan National University, Busan, Republic of Korea.
3. Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
4. Department of Occupational and Environmental Medicine, Kosin University Gospel Hospital, Republic of Korea.
5. Department of Microbiology, College of Medicine, Gachon University, Incheon, Republic of Korea.
6. Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
7. Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, Republic of Korea.
8. Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
*These authors contributed equally to this work.

Citation:
Ko DS, Kang J, Heo HJ, Kim EK, Kim K, Kang JM, Jung Y, Baek SE, Kim YH. Role of PCK2 in the proliferation of vascular smooth muscle cells in neointimal hyperplasia. Int J Biol Sci 2022; 18(13):5154-5167. doi:10.7150/ijbs.75577. https://www.ijbs.com/v18p5154.htm
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Abstract

Graphic abstract

Vascular smooth muscle cell (VSMC) proliferation is a hallmark of neointimal hyperplasia (NIH) in atherosclerosis and restenosis post-balloon angioplasty and stent insertion. Although numerous cytotoxic and cytostatic therapeutics have been developed to reduce NIH, it is improbable that a multifactorial disease can be successfully treated by focusing on a preconceived hypothesis. We, therefore, aimed to identify key molecules involved in NIH via a hypothesis-free approach. We analyzed four datasets (GSE28829, GSE43292, GSE100927, and GSE120521), evaluated differentially expressed genes (DEGs) in wire-injured femoral arteries of mice, and determined their association with VSMC proliferation in vitro. Moreover, we performed RNA sequencing on platelet-derived growth factor (PDGF)-stimulated human VSMCs (hVSMCs) post-phosphoenolpyruvate carboxykinase 2 (PCK2) knockdown and investigated pathways associated with PCK2. Finally, we assessed NIH formation in Pck2 knockout (KO) mice by wire injury and identified PCK2 expression in human femoral artery atheroma. Among six DEGs, only PCK2 and RGS1 showed identical expression patterns between wire-injured femoral arteries of mice and gene expression datasets. PDGF-induced VSMC proliferation was attenuated when hVSMCs were transfected with PCK2 siRNA. RNA sequencing of PCK2 siRNA-treated hVSMCs revealed the involvement of the Akt-FoxO-PCK2 pathway in VSMC proliferation via Akt2, Akt3, FoxO1, and FoxO3. Additionally, NIH was attenuated in the wire-injured femoral artery of Pck2-KO mice and PCK2 was expressed in human femoral atheroma. PCK2 regulates VSMC proliferation in response to vascular injury via the Akt-FoxO-PCK2 pathway. Targeting PCK2, a downstream signaling mediator of VSMC proliferation, may be a novel therapeutic approach to modulate VSMC proliferation in atherosclerosis.

Keywords: vascular smooth muscle cell proliferation, neointimal hyperplasia, atherosclerosis, PCK2, Akt-FoxO-PCK2 pathway


Citation styles

APA
Ko, D.S., Kang, J., Heo, H.J., Kim, E.K., Kim, K., Kang, J.M., Jung, Y., Baek, S.E., Kim, Y.H. (2022). Role of PCK2 in the proliferation of vascular smooth muscle cells in neointimal hyperplasia. International Journal of Biological Sciences, 18(13), 5154-5167. https://doi.org/10.7150/ijbs.75577.

ACS
Ko, D.S.; Kang, J.; Heo, H.J.; Kim, E.K.; Kim, K.; Kang, J.M.; Jung, Y.; Baek, S.E.; Kim, Y.H. Role of PCK2 in the proliferation of vascular smooth muscle cells in neointimal hyperplasia. Int. J. Biol. Sci. 2022, 18 (13), 5154-5167. DOI: 10.7150/ijbs.75577.

NLM
Ko DS, Kang J, Heo HJ, Kim EK, Kim K, Kang JM, Jung Y, Baek SE, Kim YH. Role of PCK2 in the proliferation of vascular smooth muscle cells in neointimal hyperplasia. Int J Biol Sci 2022; 18(13):5154-5167. doi:10.7150/ijbs.75577. https://www.ijbs.com/v18p5154.htm

CSE
Ko DS, Kang J, Heo HJ, Kim EK, Kim K, Kang JM, Jung Y, Baek SE, Kim YH. 2022. Role of PCK2 in the proliferation of vascular smooth muscle cells in neointimal hyperplasia. Int J Biol Sci. 18(13):5154-5167.

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