PDF(Pubmed)
Abstract：
UNASSIGNED: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear.
UNASSIGNED: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples.
UNASSIGNED: Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF.
UNASSIGNED: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.
UNASSIGNED: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples.
UNASSIGNED: Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF.
UNASSIGNED: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.
摘要：
■肺动脉高压（PH）代表射血分数保留的心力衰竭（HFpEF）的重要表型。然而,PH-HFpEF的管理具有挑战性,因为参与PH-HFpEF调节的机制尚不清楚.
■我们使用基于质谱的比较血浆蛋白质组学方法作为一种灵敏而全面的假设生成发现技术，用于分析PH-HFpEF患者和对照受试者的蛋白质。然后，我们使用体外细胞培养物验证并研究了一种已鉴定蛋白质的作用，体内动物模型，和独立的人类样本队列。
■血浆蛋白质组学在PH-HFpEF患者中发现了高蛋白质丰度水平的B2M（β2-微球蛋白）。有趣的是,在骨骼肌SIRT3(sirtuin-3)缺乏或高脂饮食诱导的PH-HFpEF小鼠中,循环和骨骼肌的B2M水平均升高.来自PH-HFpEF患者验证队列的血浆和肌肉活检发现B2M水平升高，与疾病严重程度呈正相关，尤其是静息时的肺毛细血管楔压和右心房压。外源性B2M的给药不仅促进了肺动脉血管内皮细胞的迁移/增殖，而且还增加了PCNA（增殖细胞核抗原）的表达和肺动脉血管平滑肌细胞的细胞增殖。最后,B2m缺失改善糖耐量，肺血管重塑减少，降低PH,并减轻高脂饮食诱导的PH-HFpEF小鼠的RV肥大。
■PH-HFpEF患者表现出更高的循环和骨骼肌B2M表达水平，其大小与疾病严重程度相关。我们的发现还揭示了B2M在调节肺血管增殖重塑和PH-HFpEF中的先前未知的致病作用。这些数据表明，循环和骨骼肌B2M可能是治疗PH-HFpEF的有希望的目标。
■我们使用基于质谱的比较血浆蛋白质组学方法作为一种灵敏而全面的假设生成发现技术，用于分析PH-HFpEF患者和对照受试者的蛋白质。然后，我们使用体外细胞培养物验证并研究了一种已鉴定蛋白质的作用，体内动物模型，和独立的人类样本队列。
■血浆蛋白质组学在PH-HFpEF患者中发现了高蛋白质丰度水平的B2M（β2-微球蛋白）。有趣的是,在骨骼肌SIRT3(sirtuin-3)缺乏或高脂饮食诱导的PH-HFpEF小鼠中,循环和骨骼肌的B2M水平均升高.来自PH-HFpEF患者验证队列的血浆和肌肉活检发现B2M水平升高，与疾病严重程度呈正相关，尤其是静息时的肺毛细血管楔压和右心房压。外源性B2M的给药不仅促进了肺动脉血管内皮细胞的迁移/增殖，而且还增加了PCNA（增殖细胞核抗原）的表达和肺动脉血管平滑肌细胞的细胞增殖。最后,B2m缺失改善糖耐量，肺血管重塑减少，降低PH,并减轻高脂饮食诱导的PH-HFpEF小鼠的RV肥大。
■PH-HFpEF患者表现出更高的循环和骨骼肌B2M表达水平，其大小与疾病严重程度相关。我们的发现还揭示了B2M在调节肺血管增殖重塑和PH-HFpEF中的先前未知的致病作用。这些数据表明，循环和骨骼肌B2M可能是治疗PH-HFpEF的有希望的目标。
