Talati Megha, Brittain Evan, Agrawal Vineet, Fortune Niki, Simon Katie, Shay Sheila, Zeng Xiaofang, Freeman Michael L, West James, Hemnes Anna
Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
Front Med (Lausanne). 2023 Oct 5;10:1276422. doi: 10.3389/fmed.2023.1276422. eCollection 2023.
Pulmonary arterial hypertension is a fatal cardiopulmonary disease. Leptin, a neuroendocrine hormone released by adipose tissue, has a complex relationship with cardiovascular diseases, including PAH. be an important factor linking and cardiovascular disorders. Given the published association between metabolic syndrome and RV dysfunction in PAH, we sought to determine the association between leptin and RV dysfunction. We hypothesized that in PAH-RV, leptin influences metabolic changes via leptin receptors, which can be manipulated by metformin.
Plasma leptin was measured in PAH patients and healthy controls from a published trial of metformin in PAH. Leptin receptor localization was detected in RV from PAH patients, healthy controls, animal models of PH with RV dysfunction before and after metformin treatment, and cultured cardiomyocytes with two different BMPR2 mutants by performing immunohistochemical and cell fractionation studies. Functional studies were conducted in cultured cardiomyocytes to examine the role of leptin and metformin in lipid-driven mitochondrial respiration.
In human studies, we found that plasma leptin levels were higher in PAH patients and moderately correlated with higher BMI, but not in healthy controls. Circulating leptin levels were reduced by metformin treatment, and these findings were confirmed in an animal model of RV dysfunction. Leptin receptor expression was increased in PAH-RV cardiomyocytes. In animal models of RV dysfunction and cultured cardiomyocytes with BMPR2 mutation, we found increased expression and membrane localization of the leptin receptor. In cultured cardiomyocytes with BMPR2 mutation, leptin moderately influences palmitate uptake, possibly via CD36, in a mutation-specific manner. Furthermore, in cultured cardiomyocytes, the Seahorse XFe96 Extracellular Flux Analyzer and gene expression data indicate that leptin may not directly influence lipid-driven mitochondrial respiration in BMPR2 mutant cardiomyocytes. However, metformin alone or when supplemented with leptin can improve lipid-driven mitochondrial respiration in BMPR2 mutant cardiomyocytes. The effect of metformin on lipid-driven mitochondrial respiration in cardiomyocytes is BMPR2 mutation-specific.
In PAH, increased circulating leptin can influence metabolic signaling in RV cardiomyocytes via the leptin receptor; in particular, it may alter lipid-dependent RV metabolism in combination with metformin in a mutation-specific manner and warrants further investigation.
肺动脉高压是一种致命的心肺疾病。瘦素是一种由脂肪组织释放的神经内分泌激素，它与包括肺动脉高压在内的心血管疾病有着复杂的关系，是连接肥胖与心血管疾病的一个重要因素。鉴于已发表的关于代谢综合征与肺动脉高压患者右心室功能障碍之间的关联，我们试图确定瘦素与右心室功能障碍之间的关联。我们假设在肺动脉高压合并右心室病变（PAH-RV）中，瘦素通过瘦素受体影响代谢变化，而二甲双胍可以对其进行调控。
在一项已发表的关于二甲双胍治疗肺动脉高压的试验中，测量了肺动脉高压患者和健康对照者的血浆瘦素水平。通过免疫组织化学和细胞分级分离研究，在肺动脉高压患者、健康对照者、右心室功能障碍的肺动脉高压动物模型在二甲双胍治疗前后的右心室组织，以及具有两种不同骨形态发生蛋白受体2（BMPR2）突变体的培养心肌细胞中，检测瘦素受体的定位。在培养的心肌细胞中进行功能研究，以检查瘦素和二甲双胍在脂质驱动的线粒体呼吸中的作用。
在人体研究中，我们发现肺动脉高压患者的血浆瘦素水平较高，且与较高的体重指数呈中度相关，但在健康对照者中并非如此。二甲双胍治疗可降低循环瘦素水平，这些发现也在右心室功能障碍的动物模型中得到证实。在PAH-RV心肌细胞中，瘦素受体表达增加。在右心室功能障碍的动物模型和具有BMPR2突变的培养心肌细胞中，我们发现瘦素受体的表达和膜定位增加。在具有BMPR2突变的培养心肌细胞中，瘦素可能通过CD36以突变特异性方式适度影响棕榈酸摄取。此外，在培养的心肌细胞中，海马XFe96细胞外流量分析仪和基因表达数据表明，瘦素可能不会直接影响BMPR2突变心肌细胞中脂质驱动的线粒体呼吸。然而，单独使用二甲双胍或与瘦素联合使用时，可以改善BMPR2突变心肌细胞中脂质驱动的线粒体呼吸。二甲双胍对心肌细胞中脂质驱动的线粒体呼吸的影响具有BMPR2突变特异性。
在肺动脉高压中，循环瘦素增加可通过瘦素受体影响右心室心肌细胞的代谢信号；特别是，它可能与二甲双胍以突变特异性方式联合改变右心室脂质依赖性代谢，值得进一步研究。
