Mechanical Activation of cPLA2 Impedes Fatty Acid β‐Oxidation in Vein Grafts
Abstract High‐magnitude cyclic stretch from arterial blood pressure significantly contributes to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs), leading to neointima formation in vein grafts. However, the molecular mechanisms remain unclear. This study highlights t...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202411559 |
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| author | Linwei Fan Yuanjun Tang Jian Liu Yueqi Liu Yiwei Xu Jiayu Liu Han Liu Wei Pang Yuxuan Guo Weijuan Yao Tao Zhang Qin Peng Jing Zhou |
| author_facet | Linwei Fan Yuanjun Tang Jian Liu Yueqi Liu Yiwei Xu Jiayu Liu Han Liu Wei Pang Yuxuan Guo Weijuan Yao Tao Zhang Qin Peng Jing Zhou |
| author_sort | Linwei Fan |
| collection | DOAJ |
| description | Abstract High‐magnitude cyclic stretch from arterial blood pressure significantly contributes to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs), leading to neointima formation in vein grafts. However, the molecular mechanisms remain unclear. This study highlights the critical role of cytosolic Phospholipase A2 (cPLA2)/ Yin Yang 1 (YY1)/ carnitine palmitoyltransferase 1b (CPT1B) signaling in coordinating VSMC mechanical activation by inhibiting fatty acid β‐oxidation. Metabolomic analysis showed that a 15%–1 Hz arterial cyclic stretch, compared to a 5%–1 Hz venous stretch, increased long‐chain fatty acids in VSMCs. cPLA2, identified as a mechanoresponsive molecule, produces excessive arachidonic acid (ArAc) under the 15%–1 Hz stretch, inhibiting CPT1B expression, a key enzyme in fatty acid β‐oxidation. ArAc promotes transcription factor YY1 degradation, downregulating CPT1B. Inadequate fatty acid oxidation caused by knockdown of CPT1B or YY1, or etomoxir treatment, increased nuclear membrane tension, orchestrating the activation of cPLA2. Overexpressing CPT1B or inhibiting cPLA2 reduced VSMC proliferation and migration in vein grafts, decreasing neointimal hyperplasia. This study uncovers a novel mechanism in lipid metabolic reprogramming in vein grafts, suggesting a new therapeutic target for vein graft hyperplasia. |
| format | Article |
| id | doaj-art-0e3fb015ed844de6a75203075a27ecc7 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-0e3fb015ed844de6a75203075a27ecc72025-01-20T13:04:18ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202411559Mechanical Activation of cPLA2 Impedes Fatty Acid β‐Oxidation in Vein GraftsLinwei Fan0Yuanjun Tang1Jian Liu2Yueqi Liu3Yiwei Xu4Jiayu Liu5Han Liu6Wei Pang7Yuxuan Guo8Weijuan Yao9Tao Zhang10Qin Peng11Jing Zhou12Department of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaShenzhen Bay Laboratory Shenzhen 518132 ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaInstitute of Cardiovascular Sciences School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaDepartment of Vascular Surgery Peking University People's Hospital Beijing 100044 ChinaShenzhen Bay Laboratory Shenzhen 518132 ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Peking University Beijing 100191 ChinaAbstract High‐magnitude cyclic stretch from arterial blood pressure significantly contributes to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs), leading to neointima formation in vein grafts. However, the molecular mechanisms remain unclear. This study highlights the critical role of cytosolic Phospholipase A2 (cPLA2)/ Yin Yang 1 (YY1)/ carnitine palmitoyltransferase 1b (CPT1B) signaling in coordinating VSMC mechanical activation by inhibiting fatty acid β‐oxidation. Metabolomic analysis showed that a 15%–1 Hz arterial cyclic stretch, compared to a 5%–1 Hz venous stretch, increased long‐chain fatty acids in VSMCs. cPLA2, identified as a mechanoresponsive molecule, produces excessive arachidonic acid (ArAc) under the 15%–1 Hz stretch, inhibiting CPT1B expression, a key enzyme in fatty acid β‐oxidation. ArAc promotes transcription factor YY1 degradation, downregulating CPT1B. Inadequate fatty acid oxidation caused by knockdown of CPT1B or YY1, or etomoxir treatment, increased nuclear membrane tension, orchestrating the activation of cPLA2. Overexpressing CPT1B or inhibiting cPLA2 reduced VSMC proliferation and migration in vein grafts, decreasing neointimal hyperplasia. This study uncovers a novel mechanism in lipid metabolic reprogramming in vein grafts, suggesting a new therapeutic target for vein graft hyperplasia.https://doi.org/10.1002/advs.202411559cell proliferation and migrationfatty acid β‐oxidationmechanical forcemechanosensoryvascular smooth muscle cell |
| spellingShingle | Linwei Fan Yuanjun Tang Jian Liu Yueqi Liu Yiwei Xu Jiayu Liu Han Liu Wei Pang Yuxuan Guo Weijuan Yao Tao Zhang Qin Peng Jing Zhou Mechanical Activation of cPLA2 Impedes Fatty Acid β‐Oxidation in Vein Grafts Advanced Science cell proliferation and migration fatty acid β‐oxidation mechanical force mechanosensory vascular smooth muscle cell |
| title | Mechanical Activation of cPLA2 Impedes Fatty Acid β‐Oxidation in Vein Grafts |
| title_full | Mechanical Activation of cPLA2 Impedes Fatty Acid β‐Oxidation in Vein Grafts |
| title_fullStr | Mechanical Activation of cPLA2 Impedes Fatty Acid β‐Oxidation in Vein Grafts |
| title_full_unstemmed | Mechanical Activation of cPLA2 Impedes Fatty Acid β‐Oxidation in Vein Grafts |
| title_short | Mechanical Activation of cPLA2 Impedes Fatty Acid β‐Oxidation in Vein Grafts |
| title_sort | mechanical activation of cpla2 impedes fatty acid β oxidation in vein grafts |
| topic | cell proliferation and migration fatty acid β‐oxidation mechanical force mechanosensory vascular smooth muscle cell |
| url | https://doi.org/10.1002/advs.202411559 |
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