Research suggests that the enzyme phosphoenolpyruvate carboxykinase 2 and its gene play a role in the development of vascular injury and atherosclerosis

Atherosclerosis is a deadly disease; research suggests that proliferation of vascular smooth muscle cells (VSMCs) and formation of a neointimal layer along the inner lining of arteries play a major role in the progression of this disease. However, the factors that control these processes were unknown so far. Now, researchers from Korea report an enzyme whose inhibition attenuates VSMC proliferation. Targeting this enzyme could thus present a new avenue for the treatment of atherosclerosis.

Atherosclerosis—the build-up of plaques, or atheromas, along the inner lining of arteries—can damage arteries and lead to serious complications like cardiac arrest, stroke, or even death if left untreated. It occurs when there is a proliferation of vascular smooth muscular cells (VSMCs) and formation of a layer (known as neointima) along arterial walls, eventually leading to their stenosis (i.e., narrowing), and a disruption of blood flow. It is treated by placing stents which widen the arteries. However, these are not always successful in the long term. For example, 30%–40% of stents placed in femoropopliteal arteries re-stenose within 2 years of the procedure. Drug-coated balloons which provide the dual benefit of widening an artery while locally delivering drugs to prevent formation of the neointima—also known as neointimal hyperplasia or NIH—have been used, but there is still a need for better therapies. And for better therapies, we need a better understanding of the process that leads to NIH, VSMC proliferation, and vascular injury. What factors control this process?

A group of researchers from Korea, led by Professor Yun Hak Kim of Pusan National University, set out to find answers. Their study, which was published in Volume 18, Issue 13 of the International Journal of Biological Sciences on 8 August 2022, describes how a particular gene—phosphoenolpyruvate carboxykinase 2 (PCK2)—and the enzyme that it encodes control the proliferation of VSMCs and development of NIH in samples of vascular injury and atheromas. Previous studies have reported that PCK2 is involved in glucose metabolism and promotes tumor growth and cell proliferation.

Their first aim was to find genes which were differentially expressed in carotid atheromas. Not wanting to limit their findings, they started with a hypothesis-free approach, examining diseased and healthy gene profiles from the GSE (Gene Expression Omnibus) series. Says Prof. Kim, “We found six genes that were differentially expressed in disease, three of which were upregulated. The expression of two of these—including PCK2—was associated with NIH in mouse models of vascular injury. Moreover, inhibition of PCK2 reduced the proliferation of VSMCs.”

Further mechanistic experiments revealed two signaling pathways which were associated with PCK2. These were the PI3K-Akt and FoxO pathways. Akt, a protein, activates cell growth; FoxO aids the expression of genes during cell proliferation. It is via these pathways that PCK2 and its gene regulate VSMC proliferation after vascular injury, the team reported.

Prof. Kim also tells us, “VSMCs in human atheromas have a very high expression of PCK2. And given the findings of our study, we believe this enzyme can also be targeted to prevent arterial re-stenosis after stent placement and improve outcomes of vascular injury treatment.” Let’s hope that the team’s findings lead to an improved treatment modality for atherosclerosis!

Reference

Title of original paper: Role of PCK2 in the proliferation of vascular smooth muscle cells in neointimal hyperplasia

Journal: International Journal of Biological Sciences

DOI: 10.7150/ijbs.75577

Authors: Dai Sik Ko^1*, Junho Kang^2*, Hye Jin He³, Eun Kyoung Kim³, Kihun Kim⁴, Jin Mo Kang¹, YunJae Jung^5,6,7, Seung Eun Baek³, and Yun Hak Kim^3,8

Affilitations: ¹: Division of Vascular Surgery, Department of General Surgery, Gachon University Gil Medical Center

²: Medical Research Institute, Pusan National University

³: Department of Anatomy, School of Medicine, Pusan National University

⁴: Department of Occupational and Environmental Medicine, Kosin University Gospel Hospital

⁵: Department of Microbiology, College of Medicine, Gachon University

⁶: Lee Gil Ya Cancer and Diabetes Institute, Gachon University

⁷: Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University

⁸: Department of Biomedical Informatics, School of Medicine, Pusan National University

*Corresponding author’s email: yunhak10510@pusan.ac.kr

 Website:                             https://yunhakkim.pusan.ac.kr/

ORCID id: 0000-0002-9796-8266

About Pusan National University

Pusan National University, located in Busan, South Korea, was founded in 1946 and is now the no. 1 national university of South Korea in research and educational competency. The multi-campus university also has other smaller campuses in Yangsan, Miryang, and Ami. The university prides itself on the principles of truth, freedom, and service, and has approximately 30,000 students, 1200 professors, and 750 faculty members. The university is composed of 14 colleges (schools) and one independent division, with 103 departments in all.

Website: https://www.pusan.ac.kr/eng/Main.do

About the author

Prof. Yun Hak Kim is an associate professor at the Department of Anatomy and Department of Biomedical Informatics, School of Medicine, Pusan National University. He received his Ph.D. from Pusan University in 2016 and has won several research grants and academic awards, including a Commendation from the Minister of Science and ICT (Ministry of Science and ICT). His work focusses on developing new biomarkers for several diseases using genomic big data and validating these biomarkers.