1. Academic Validation
  2. T lymphocyte-derived extracellular vesicles aggravate abdominal aortic aneurysm by promoting macrophage lipid peroxidation and migration via pyruvate kinase muscle isozyme 2

T lymphocyte-derived extracellular vesicles aggravate abdominal aortic aneurysm by promoting macrophage lipid peroxidation and migration via pyruvate kinase muscle isozyme 2

  • Redox Biol. 2022 Apr;50:102257. doi: 10.1016/j.redox.2022.102257.
Guohui Dang 1 Tianrun Li 2 Dongmin Yang 1 Guangxin Yang 2 Xing Du 1 Juan Yang 1 Yutong Miao 1 Lulu Han 1 Xiaolong Ma 1 Yuwei Song 1 Bo Liu 1 Xuan Li 2 Xian Wang 1 Juan Feng 3
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
  • 2 Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing 100191, China.
  • 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China; Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing 100191, China; Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China. Electronic address: juanfeng@bjmu.edu.cn.
Abstract

T lymphocyte and macrophage infiltration in the aortic wall is critical for abdominal aortic aneurysm (AAA). However, how T lymphocytes interact with macrophages in the pathogenesis of AAA remains largely uncharacterized. In an elastase-induced murine AAA model, we first found that the expression of Pyruvate Kinase muscle isozyme 2 (PKM2), the last rate-limiting Enzyme in glycolysis, was increased in infiltrated T lymphocytes of vascular lesions. T lymphocyte-specific PKM2 deficiency in mice (LckCrePKM2fl/fl) or intraperitoneal administration of the sphingomyelinase inhibitor GW4869 caused a significant attenuation of the elastase-increased aortic diameter, AAA incidence, elastic fiber disruption, Matrix Metalloproteinases (MMPs) expression, and macrophage infiltration in the vascular adventitia compared with those in PKM2fl/fl mice. Mechanistically, extracellular vesicles (EVs) derived from PKM2-activated T lymphocytes elevated macrophage iron accumulation, lipid peroxidation, and migration in vitro, while macrophages treated with EVs from PKM2-null T lymphocytes or pretreated with the lipid peroxidation inhibitors ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), or the iron chelating agent deferoxamine mesylate (DFOM) reversed these effects. In vascular lesions of elastase-induced LckCrePKM2fl/fl mice with AAA, the oxidant system weakened, with downregulated 4-hydroxynonenal (4-HNE) levels and strengthened antioxidant defense systems with upregulated Glutathione Peroxidase 4 (GPX4) and cystine/glutamate antiporter solute carrier family 7 member 11 (Slc7a11) expressions in macrophages. High-throughput metabolomics showed that EVs derived from PKM2-activated T lymphocytes contained increased levels of polyunsaturated fatty acid (PUFA)-containing Phospholipids, which may provide abundant substrates for lipid peroxidation in target macrophages. More importantly, upregulated T lymphocyte PKM2 expression was also found in clinical AAA subjects, and EVs isolated from AAA patient plasma enhanced macrophage iron accumulation, lipid peroxidation, and migration ex vivo. Therefore, from cell-cell crosstalk and metabolic perspectives, the present study shows that PKM2-activated T lymphocyte-derived EVs may drive AAA progression by promoting macrophage redox imbalance and migration, and targeting the T lymphocyte-EV-macrophage axis may be a potential strategy for early warning and treating AAA.

Keywords

Abdominal aortic aneurysm; Extracellular vesicles; Lipid peroxidation; Macrophage migration; Pyruvate kinase muscle isozyme 2.

Figures
Products