Three-Dimensional Micro Computed Tomography Analysis of the Lung Vasculature and Differential Adipose Proteomics in the Sugen/Hypoxia Rat Model of Pulmonary Arterial Hypertension
Three-Dimensional Micro Computed Tomography Analysis of the Lung Vasculature and Differential Adipose Proteomics in the Sugen/Hypoxia Rat Model of Pulmonary Arterial Hypertension
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DOI：
10.1086/688931
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发表时间：
2016-10
影响因子：
2.6
通讯作者：
K. Shields;K. Verdelis;M. Passineau;Erin M. Faight;L. Zourelias;Changgong Wu;R. Chong;R. Benza
中科院分区：
文献类型：
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作者：
K. Shields;K. Verdelis;M. Passineau;Erin M. Faight;L. Zourelias;Changgong Wu;R. Chong;R. Benza
肺动脉高压(PAH)是一种罕见的疾病，其特征是显著的血管重构。肥胖的流行引起了人们对微小内脏脂肪组织库与局部炎症条件之间的关系的极大兴趣，这些炎症条件可能将代谢、先天免疫和血管重构联系在一起。本研究使用新型的显微计算机断层扫描(MicroCT)三维模型来研究重度PAH大鼠肺血管重塑的程度，并利用差异蛋白质组学来确定小内脏脂肪功能障碍。SD大鼠皮下注射血管内皮生长因子受体阻滞剂(SUGEN 5416)，然后进行3周的低氧暴露(SU/Hyp)。缺氧12周后，MicroCT分析显示，SU/Hyp组血管与总组织体积的比值减少(平均值±标准差：0.27±0.066；P=0.02)，血管间距增加(0.37±0.062 mm；P=0.02)，与对照组(0.34±0.084和0.30±0.072 mm)相比，差异有统计学意义(P=0.02)。差异蛋白质组学检测到SU/Hyp的心脏脂肪中补体蛋白3(C3；SU/Hyp：对照比=2.86)和脂肪组织特异性脂肪酸结合蛋白4(FABP4，2.66)表达上调。肺血管的显著重塑证实了SU/Hyp大鼠在模拟人类PAH方面的有效性。心脏脂肪中C3和FABP4表达上调，提示内脏脂肪功能障碍。C3与血管僵硬有关，FABP4抑制过氧化物酶体增殖物激活受体，后者是脂肪功能的主要调节因子，已知在PAH中下调。这些发现揭示了SU/Hyp模型中的小内脏脂肪组织在PAH的病理生理学中为血管重塑和脂肪功能障碍提供了机制联系。
Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling. The obesity epidemic has produced great interest in the relationship between small visceral adipose tissue depots producing localized inflammatory conditions, which may link metabolism, innate immunity, and vascular remodeling. This study used novel micro computed tomography (microCT) three-dimensional modeling to investigate the degree of remodeling of the lung vasculature and differential proteomics to determine small visceral adipose dysfunction in rats with severe PAH. Sprague-Dawley rats were subjected to a subcutaneous injection of vascular endothelial growth factor receptor blocker (Sugen 5416) with subsequent hypoxia exposure for 3 weeks (SU/hyp). At 12 weeks after hypoxia, microCT analysis showed a decrease in the ratio of vascular to total tissue volume within the SU/hyp group (mean ± standard deviation: 0.27 ± 0.066; P = 0.02) with increased vascular separation (0.37 ± 0.062 mm; P = 0.02) when compared with the control (0.34 ± 0.084 and 0.30 ± 0.072 mm). Differential proteomics detected an up-regulation of complement protein 3 (C3; SU/hyp: control ratio = 2.86) and the adipose tissue–specific fatty acid binding protein-4 (FABP4, 2.66) in the heart adipose of the SU/hyp. Significant remodeling of the lung vasculature validates the efficacy of the SU/hyp rat for modeling human PAH. The upregulation of C3 and FABP4 within the heart adipose implicates small visceral adipose dysfunction. C3 has been associated with vascular stiffness, and FABP4 suppresses peroxisome proliferator–activated receptor, which is a major regulator of adipose function and known to be downregulated in PAH. These findings reveal that small visceral adipose tissue within the SU/hyp model provides mechanistic links for vascular remodeling and adipose dysfunction in the pathophysiology of PAH.