A potential adverse role for leptin and cardiac leptin receptor in the right ventricle in pulmonary arterial hypertension: effect of metformin is BMPR2 mutation-specific.
A potential adverse role for leptin and cardiac leptin receptor in the right ventricle in pulmonary arterial hypertension: effect of metformin is BMPR2 mutation-specific.
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DOI：
10.3389/fmed.2023.1276422
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发表时间：
2023
影响因子：
3.9
通讯作者：
Hemnes A
中科院分区：
文献类型：
--
作者：
Talati M;Brittain E;Agrawal V;Fortune N;Simon K;Shay S;Zeng X;Freeman ML;West J;Hemnes A
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，与包括多环芳烃在内的心血管疾病有着复杂的关系。瘦素被认为是联系代谢综合征和心血管疾病的重要因素。鉴于已发表的PAH代谢综合征与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PAH-RV中，瘦素通过瘦素受体影响代谢变化，这可以被二甲双胍操纵。在PAH患者和健康对照中测量血浆瘦素，这是一项已发表的二甲双胍治疗PAH的试验。通过免疫组化和细胞分离研究，在PAH患者、健康对照、二甲双胍治疗前后伴有RV功能障碍的PH动物模型和培养的两种不同BMPR2突变体的心肌细胞中检测瘦素受体定位。在培养的心肌细胞中进行了功能研究，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PAH患者的血浆瘦素水平较高，并且与较高的BMI有中度相关性，但在健康对照中则没有。二甲双胍治疗降低了循环瘦素水平，这些发现在RV功能障碍的动物模型中得到了证实。PAH-RV心肌细胞瘦素受体表达升高。在RV功能障碍动物模型和BMPR2突变培养心肌细胞中，我们发现瘦素受体的表达和膜定位增加。在培养的BMPR2突变的心肌细胞中，瘦素可能通过CD36以突变特异性的方式适度影响棕榈酸盐摄取。此外，在培养的心肌细胞中，Seahorse XFe96细胞外通量分析仪和基因表达数据表明，瘦素可能不会直接影响BMPR2突变型心肌细胞中脂质驱动的线粒体呼吸。然而，单用二甲双胍或补充瘦素可以改善BMPR2突变型心肌细胞中脂质驱动的线粒体呼吸。二甲双胍对心肌细胞脂质驱动的线粒体呼吸的影响是BMPR2突变特异性的。在PAH中，循环瘦素增加可以通过瘦素受体影响RV心肌细胞的代谢信号；特别是，它可能以突变特异性的方式改变脂质依赖性RV代谢与二甲双胍联合，值得进一步研究。
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. Leptin is thought to be an important factor linking metabolic syndrome 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.
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影响因子：
9.3
作者：
Al-Attas OS;Al-Daghri NM;Al-Rubeaan K;da Silva NF;Sabico SL;Kumar S;McTernan PG;Harte AL
通讯作者：
Harte AL
影响因子：
2.6
作者：
Tonelli AR;Fares WH;Dakkak W;Rao Y;Zhou X;Dweik RA
通讯作者：
Dweik RA
影响因子：
8.2
作者：
An, D.;Kewalramani, G.;Rodrigues, B.
通讯作者：
Rodrigues, B.
DOI：
10.1016/j.biocel.2016.01.002
发表时间：
2016-03-01
影响因子：
4
作者：
del Mar Blanquer-Rossello, Ma;Oliver, Jordi;Roca, Pilar
通讯作者：
Roca, Pilar
影响因子：
9.8
作者：
Fruehwald-Schultes, B;Oltmanns, KM;Peters, A
通讯作者：
Peters, A