Sheng Le1,2, Hao Zhang1,2, Xiaofan Huang1, Shu Chen1, Jia Wu3, Shanshan Chen1, XiangChao Ding1, Shanshan Chen1, Jing Zhao1, Heng Xu1, Jikai Cui1, Yanqiang Zou1, Jizhang Yu1, Lang Jiang1, Jie Wu1, Ping Ye4, Jiahong Xia1. 1. Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2. The authers Sheng Le and Hao Zhang contributed equally to this article as first authors. 3. Key Laboratory for Molecular Diagnosis of Hubei Province, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 4. Department of Cardiology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract
BACKGROUND: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far. APPROACH AND RESULTS: We analyzed aortic tissues from TAAD patients and the β-aminopropionitrile fumarate (BAPN)-induced mouse model of TAAD and observed elevated levels of PKM2 in the aortic lesions of both. Treatment with the PKM2 activator TEPP-46 markedly attenuated the progression of TAAD in the mouse model as demonstrated by decreased morbidity and luminal diameter of the aorta. In addition, the thoracic aortas of the BAPN-induced mice showed reduced monocytes and macrophages infiltration and lower levels of IL-1β, MMPs, and ROS when treated with TEPP-46. Furthermore, TEPP-46 treatment also suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome by downregulating p-STAT3 and HIF1-α. CONCLUSION: Pyruvate kinase M2 plays a protective role in TAAD development, and its activation is a promising therapeutic strategy against the progression of TAAD.
BACKGROUND: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far. APPROACH AND RESULTS: We analyzed aortic tissues from TAAD patients and the β-aminopropionitrile fumarate (BAPN)-induced mouse model of TAAD and observed elevated levels of PKM2 in the aortic lesions of both. Treatment with the PKM2 activator TEPP-46 markedly attenuated the progression of TAAD in the mouse model as demonstrated by decreased morbidity and luminal diameter of the aorta. In addition, the thoracic aortas of the BAPN-induced mice showed reduced monocytes and macrophages infiltration and lower levels of IL-1β, MMPs, and ROS when treated with TEPP-46. Furthermore, TEPP-46 treatment also suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome by downregulating p-STAT3 and HIF1-α. CONCLUSION:Pyruvate kinase M2 plays a protective role in TAAD development, and its activation is a promising therapeutic strategy against the progression of TAAD.
Authors: Maria Apostolidi; Ioannis A Vathiotis; Viswanathan Muthusamy; Patricia Gaule; Brandon M Gassaway; David L Rimm; Jesse Rinehart Journal: Cancer Res Date: 2021-06-21 Impact factor: 12.701