Effects of attenuated leptin signaling pathways on cardiac function under high-altitude hypoxia

Background: High-altitude hypoxia significantly impacts cardiovascular function, but the effects of adipose/metabolic factors on cardiovascular regulation remain unclear. Thus, a deeper understanding of adipose/metabolic factors’ role in cardiovascular function changes is needed. Methods: We assessed lung ventilation function, cardiovascular function, electrocardiogram, plasma CK-MB, sPecam-1, and 11 plasma adipose/metabolic factors in expeditioners at Antarctic Kunlun Station (4087m). To investigate adipose/metabolic factors’ effects and mechanisms on cardiac function, we constructed a rat model exposed to simulated hypobaric hypoxia (5000 m) with the same oxygen concentration as Kunlun Station. Echocardiography, ELISA, histology, and gene and protein expression studies were employed to examine cardiac function changes, pathological alterations, and leptin’s role in cardiac pathology under acute and chronic hypoxic exposure. Results: The Antarctic ice plateau environment significantly altered lung ventilation function, weakened cardiac pumping and contractile function, increased systematic vascular resistance (SVR), induced adaptive changes in cardiac conduction, significantly increased plasma CK-MB and Pecam-1, and significantly reduced plasma leptin, resistin, insulin, and lipocalin-2 levels. Decreased leptin was significantly correlated to cardiopulmonary function. Rats chronically exposed to simulated hypobaric hypoxia at 5000m exhibited pulmonary arterial hypertension (PAH), right ventricular hypertrophy (RVH), impaired left ventricular systolic and diastolic function, and significant deteriorated left ventricular global longitudinal strain (GLS), lateral and radial strains of the myocardium, with increased plasma CK-MB and sPecam-1 in hypoxic rats. Protein levels of leptin/ob-Rb, JAK2/STAT3, PI3K/AKT/GSK3β, and ERK/JNK were decreased in biventricular myocardial tissues of chronic hypoxia-exposed rats, accompanied by increased myocytes hypertrophy, fibrosis, lipid deposition, cell apoptosis, and mitochondrial dysfunction, and decreased metabolic gene levels. Left ventricular transcriptome analysis revealed that decreased myocardial leptin in hypoxic rats regulated cardiac pathology via down-regulated genes related to circadian rhythm, sodium/potassium ion transport, and cell skeleton. Conclusion: Our findings suggest that leptin is a crucial metabolic factor in regulating cardiac pathological changes and cardiac contractile and diastolic function under high altitudes. These regulatory pathways may involve leptin's classical signaling pathways and genes related to circadian rhythm, sodium/potassium ion transport, and cell skeleton in the heart.研究背景：高海拔低氧可显著影响心血管功能，但脂肪组织/代谢因子对心血管调节的作用机制仍不明确。因此，亟需深入解析脂肪组织/代谢因子在心血管功能改变中的作用。研究方法：我们对南极昆仑站（海拔4087m）的科考队员开展了肺通气功能、心血管功能、心电图、血浆肌酸激酶同工酶MB（CK-MB）、可溶性血小板内皮细胞黏附分子1（sPecam-1）及11种血浆脂肪组织/代谢因子的检测。为探究脂肪组织/代谢因子对心脏功能的作用及机制，我们构建了模拟低气压低氧（海拔5000m，氧浓度与昆仑站一致）的大鼠模型。本研究采用超声心动图、酶联免疫吸附实验（ELISA）、组织学分析以及基因与蛋白表达检测，探究急、慢性低氧暴露下心脏功能变化、病理改变及瘦素（leptin）在心脏病理进程中的作用。研究结果：南极冰原高原环境可显著改变肺通气功能，削弱心脏泵血与收缩功能，升高系统性血管阻力（systemic vascular resistance, SVR），诱发心脏传导适应性改变；同时显著升高血浆CK-MB与血小板内皮细胞黏附分子1（Pecam-1）水平，显著降低血浆瘦素、抵抗素（resistin）、胰岛素（insulin）及脂质运载蛋白2（lipocalin-2）水平。血浆瘦素水平降低与心肺功能显著相关。长期暴露于海拔5000m模拟低气压低氧环境的大鼠可出现肺动脉高压（pulmonary arterial hypertension, PAH）、右心室肥厚（right ventricular hypertrophy, RVH）、左心室收缩与舒张功能受损，左心室整体纵向应变（global longitudinal strain, GLS）及心肌侧壁、径向应变显著恶化，且低氧大鼠血浆CK-MB与sPecam-1水平升高。慢性低氧暴露大鼠双侧心室心肌组织中瘦素/瘦素受体b（ob-Rb）、JAK2/STAT3、PI3K/AKT/GSK3β及ERK/JNK的蛋白水平均降低，同时伴随心肌细胞肥大、纤维化、脂质沉积、细胞凋亡、线粒体功能障碍及代谢基因水平降低。左心室转录组分析显示，低氧大鼠心肌内瘦素水平降低可通过下调与昼夜节律、钠钾离子转运及细胞骨架相关的基因，调控心脏病理进程。研究结论：本研究结果表明，瘦素是高海拔环境下调控心脏病理改变及心脏收缩、舒张功能的关键代谢因子。其调控通路可能涉及心脏内瘦素经典信号通路及与昼夜节律、钠钾离子转运、细胞骨架相关的基因。