Qu Yao, Liu Zhi-Xue, Zheng Xiao-Xu, Wu Sheng-Nan, An Jun-Qing, Zou Ming-Hui, Zhang Zhi-Ren
Department of Cardiology, Harbin Medical University Cancer Hospital, NHC Key Laboratory of Cell Transplantation, Department of Cardiology, Central Laboratory, The First Affiliated Hospital of Harbin Medical University, Institute of Metabolic Disease, Heilongjiang Academy of Medical Sciences, Heilongjiang Key Laboratory for Metabolic Disorder & Cancer Related Cardiovascular Diseases, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, China; Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA.
Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA.
J Mol Cell Cardiol. 2025 Mar;200:45-60. doi: 10.1016/j.yjmcc.2025.01.005. Epub 2025 Jan 21.
Treatment of cancer patients with tyrosine kinase inhibitors (TKIs) often results in hypertension, but the underlying mechanism remains unclear. This study aimed to examine the role of mitochondrial morphology and function, particularly mitochondria-associated endoplasmic reticulum membranes (MAMs), in sunitinib-induced hypertension.
Both in vitro and in vivo experiments performed to assesse reactive oxygen species (ROS), nitric oxide (NO), endothelium-dependent vasorelaxation, systemic blood pressure, and mitochondrial function in human umbilical vein endothelial cells (HUVECs) and C57BL/6 mouse aortic endothelial cells, under vehicle or sunitinib treatment condition.
Sunitinib increased mitochondrial ROS accumulation, decreased oxygen consumption rate, ATP production, and mitochondrial calcium ([Ca]) levels, and impaired endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) signaling in HUVECs. In addition, sunitinib also decreased mitochondrial membrane potential, elongated mitochondria, and reduced MAMs. Remarkably, these effects were reversed by an adeno-virus linker (Ad-linker) that reinforces MAMs. Engineered augmentation of MAMs using AAV-FLT1-linker significantly mitigated sunitinib-induced hypertension, by restoring endothelium-dependent relaxation in mice, highlighting the crucial role of MAMs in this process. Further analyses revealed that sunitinib enhanced Akt-mediated expression of mitofusin 2 (MFN2), causing mitochondrial elongation, and induced dephosphorylation of inositol 1,4,5-trisphosphate receptor type 1 (IPR1) at residues Y1737/Y1738, reducing [Ca]. Our study suggests that increased MFN2 expression and IPR1 dephosphorylation are critical in sunitinib-induced MAMs reduction and [Ca] homeostasis.
Sunitinib induces mitochondrial dysfunction, Akt/MFN2-mediated decrease in MAMs and mitochondrial elongation, and IPR1 dephosphorylation in endothelial cells, leading to endothelial dysfunction and hypertension. Our results provide the potential therapeutic targets for combating TKI-induced hypertension.
用酪氨酸激酶抑制剂（TKIs）治疗癌症患者常导致高血压，但其潜在机制仍不清楚。本研究旨在探讨线粒体形态和功能，特别是线粒体相关内质网膜（MAMs）在舒尼替尼诱导的高血压中的作用。
在给予载体或舒尼替尼治疗的条件下，对人脐静脉内皮细胞（HUVECs）和C57BL/6小鼠主动脉内皮细胞进行体外和体内实验，以评估活性氧（ROS）、一氧化氮（NO）、内皮依赖性血管舒张、全身血压和线粒体功能。
舒尼替尼增加了HUVECs中线粒体ROS的积累，降低了氧消耗率、ATP产生和线粒体钙（[Ca]）水平，并损害了内皮型一氧化氮合酶（eNOS）和一氧化氮（NO）信号传导。此外，舒尼替尼还降低了线粒体膜电位，使线粒体延长，并减少了MAMs。值得注意的是，一种增强MAMs的腺病毒连接体（Ad-linker）逆转了这些效应。使用腺相关病毒-FLT1连接体（AAV-FLT1-linker）对MAMs进行工程增强，通过恢复小鼠内皮依赖性舒张，显著减轻了舒尼替尼诱导的高血压，突出了MAMs在此过程中的关键作用。进一步分析表明，舒尼替尼增强了Akt介导的线粒体融合蛋白2（MFN2）的表达，导致线粒体延长，并诱导1型肌醇1,4,5-三磷酸受体（IPR1）在Y1737/Y1738位点去磷酸化，降低了[Ca]。我们的研究表明，MFN2表达增加和IPR1去磷酸化在舒尼替尼诱导的MAMs减少和[Ca]稳态中起关键作用。
舒尼替尼诱导内皮细胞线粒体功能障碍、Akt/MFN2介导的MAMs减少和线粒体延长以及IPRl去磷酸化，导致内皮功能障碍和高血压。我们的结果为对抗TKI诱导的高血压提供了潜在的治疗靶点。
