2. Academic Validation
  3. Rap1GAP exacerbates myocardial infarction by regulating the AMPK/SIRT1/NF-κB signaling pathway

Rap1GAP exacerbates myocardial infarction by regulating the AMPK/SIRT1/NF-κB signaling pathway

  • Cell Signal. 2024 Feb 4:117:111080. doi: 10.1016/j.cellsig.2024.111080.
Tiantian Shan 1,  Xiaoying Li 2,  Wenzhi Xie 3,  Shaoqin Wang 4,  Yan Gao 5,  Yan Zheng 6,  Guohai Su 3,  Ying Li 6,  Zhuo Zhao 7
Affiliations

Affiliations

  • 1 Department of Cardiology, Jinan Central Hospital, Shandong University, Jinan 250013, China; Research Center of Translational Medicine, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China.
  • 2 Research Center of Translational Medicine, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China; Department of Emergency, Jinan Central Hospital, Jinan 250013, China; Department of Emergency, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China.
  • 3 Department of Cardiology, Jinan Central Hospital, Shandong University, Jinan 250013, China; Department of Cardiology, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China.
  • 4 Department of Emergency, Jinan Central Hospital, Jinan 250013, China; Department of Emergency, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China.
  • 5 Department of Cardiology, Qingdao Medical College, Qingdao University, Qingdao 266073, China.
  • 6 Research Center of Translational Medicine, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China.
  • 7 Department of Cardiology, Jinan Central Hospital, Shandong University, Jinan 250013, China; Department of Cardiology, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China. Electronic address: zhaozhuo1230@163.com.
PMID: 38320624 DOI: 10.1016/j.cellsig.2024.111080
Abstract

Rap1 GTPase-activating protein (Rap1GAP) is an important tumor suppressor. The purpose of this study was to investigate the role of Rap1GAP in myocardial infarction (MI) and its potential mechanism. Left anterior descending coronary artery ligation was performed on cardiac-specific Rap1GAP conditional knockout (Rap1GAP-CKO) mice and control mice with MI. Seven days after MI, Rap1GAP expression in the hearts of control mice peaked, the expression of proapoptotic markers (Bax and cleaved Caspase-3) increased, the expression of antiapoptotic factors (Bcl-2) decreased, and the expression of the inflammatory factors IL-6 and TNF-α increased; thus, Apoptosis occurred, inflammation, infarct size, and left ventricular dysfunction increased, while the heart changes caused by MI were alleviated in Rap1GAP-CKO mice. Mouse heart tissue was obtained for transcriptome Sequencing, and gene set enrichment analysis (GSEA) was used to analyze Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We found that Rap1GAP was associated with the AMPK and NF-κB signaling pathways and that Rap1GAP inhibited AMPK/SIRT1 and activated the NF-κB signaling pathway in model Animals. Similar results were observed in primary rat myocardial cells subjected to oxygen-glucose deprivation (OGD) to induce ischemia and hypoxia. Activating AMPK with the AMPK Activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reversed the damage caused by Rap1GAP overexpression in cardiomyocytes. In addition, the coimmunoprecipitation results showed that exogenous Rap1GAP interacted with AMPK. Rap1GAP was verified to regulate the AMPK SIRT1/NF-κB signaling pathway and exacerbate the damage to myocardial cells caused by ischemia and hypoxia. In conclusion, our results suggest that Rap1GAP promotes MI by modulating the AMPK/SIRT1/NF-κB signaling pathway and that Rap1GAP may be a therapeutic target for MI treatment in the future.

Keywords

AMPK/SIRT1/NF-κB signaling pathway; Apoptosis; Inflammation; Myocardial infarction; Oxidative stress; Rap1GAP.

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