Shields Kelly J, Verdelis Kostas, Passineau Michael J, Faight Erin M, Zourelias Lee, Wu Changgong, Chong Rong, Benza Raymond L
Lupus Center of Excellence, Autoimmunity Institute, Department of Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
Craniofacial Regeneration Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Pulm Circ. 2016 Dec;6(4):586-596. doi: 10.1086/688931.
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; = 0.02) with increased vascular separation (0.37 ± 0.062 mm; = 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.
肺动脉高压（PAH）是一种以显著血管重塑为特征的罕见疾病。肥胖流行引发了人们对产生局部炎症状态的小内脏脂肪组织库之间关系的极大兴趣，这种关系可能将代谢、先天免疫和血管重塑联系起来。本研究使用新型微型计算机断层扫描（microCT）三维建模来研究肺血管系统的重塑程度，并采用差异蛋白质组学来确定重度PAH大鼠的小内脏脂肪功能障碍。将Sprague-Dawley大鼠皮下注射血管内皮生长因子受体阻滞剂（Sugen 5416），随后暴露于低氧环境3周（SU/低氧组）。低氧12周后，microCT分析显示，与对照组相比，SU/低氧组血管与总组织体积的比值降低（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）（对照组分别为0.34±0.084和0.30±0.072 mm）。差异蛋白质组学检测到SU/低氧组心脏脂肪中补体蛋白3（C3；SU/低氧组∶对照组比值 = 2.86）和脂肪组织特异性脂肪酸结合蛋白4（FABP4，2.66）上调。肺血管系统的显著重塑证实了SU/低氧大鼠用于模拟人类PAH的有效性。心脏脂肪中C3和FABP4的上调提示小内脏脂肪功能障碍。C3与血管僵硬度有关，FABP4抑制过氧化物酶体增殖物激活受体，而过氧化物酶体增殖物激活受体是脂肪功能的主要调节因子，已知在PAH中下调。这些发现表明，SU/低氧模型中的小内脏脂肪组织为PAH病理生理学中的血管重塑和脂肪功能障碍提供了机制联系。
