管周脂肪功能异常导致Perilipin缺失小鼠发生高血压的机制

All arteries are surrounded by a significant amount of perivascular adipose tissue, which has long been considered to serve primarily a supportive purpose. The studies in recent ten years show that the presence of perivascular adipose tissue decreases contractile responses to various vasoconstrictive agents, because perivascular fat can produce unidentified adipocyte derived relaxing factor as a critical regulator of vascular function. Perilipin-1 is the most abundant protein at the surface of the lipid droplets only in adipocyte, and regulates optimal lipid storage and triglyceride hydrolysis and release of free fatty acids from adipocytes to the circulation. Disruption of perilipin-1 gene in human and mice primarily disrupt adipose tissue function and cause low adiposity histologically like in lipodystrophy, but high basal lipolysis and fatty acid release from the adipocytes like in obesity. We identified that Perilipin-1 null mice occur hypertension, accompanied with the dysfunctions of adipose tissue. Because Perilipin-1 does not exist in vascular tissue and cell but expresses specifically in adipocytes, its deficiency may not affect blood vessels in situ. We hypotheses that perivascular adipose tissue dysfunction confers dysregulated local productions of inflammatory adipokines and vasoconstrictive hormones and thereby no long antagonizes vasoconstriction but in turn, confers a tonic vascular contractile response, which may be the basis for the hypertension occurred in Perilipin-1 null mice. Therefore, the aims of this proposal focus on how perivascular adipose tissue dysfunction affects vascular remodeling and vasoconstriction, and hence, early onset of hypertension, in Perilipin-1 null mice. Adipose-tissue dysfunction and vascular dysfunction and hypertension in Perilipin-1 null mice may mimic and mechanistically explain that occurring in obesity and lipodystrophy, two typical diseases of adipose tissue dysfunction.

管周脂肪紧密包裹于几乎所有的动脉血管的外膜周围，为血管提供机械支持固定和营养，近来发现其有抗血管收缩作用。Perilipin-1(Plin1)特异表达于脂肪细胞的脂滴表面，调节脂肪生成与分解；它的缺失导致类似脂肪营养不良症的脂肪组织减少表型，和类似肥胖症的脂肪分解与脂肪酸释放增加等脂肪功能紊乱。我们意外发现Plin1缺失小鼠发生高血压，但全身性调节因素如水盐代谢和激素正常。Plin1在血管组织不表达,因而无血管原位调节作用。我们推测Plin1缺失导致管周脂肪功能紊乱，局部脂肪因子和血管活性物质分泌失调、脂肪酸氧化过度产生氧化应激损伤，可损害毗邻血管平滑肌或/和内皮细胞，导致血管稳态失衡与张力调节异常，进而导致高血压发生。探讨病理条件下管周脂肪对血管稳态和血压调节的影响，有助于从新的视角解释脂肪功能紊乱性疾病如肥胖、脂肪营养不良症、特别是Plin1基因突变病人伴发高血压的病理生理机制。

管周脂肪紧密包裹于几乎所有的动脉血管的外膜周围，为血管提供机械支持固定和营养，近年来认为管周脂肪具有直接的抗血管收缩功能。Perilipin-1 (Plin1)是只特异表达于脂肪细胞的脂滴包被蛋白，主要功能是调节脂滴生成和脂肪分解；Plin1不在血管组织细胞表达。Plin1基因缺失导致脂肪组织功能紊乱，表现为脂肪减少但基础脂肪分解增加。我们发现Plin1-/-小鼠血管结构和张力调节异常，并发生高血压。Plin1缺失的管周脂肪功能紊乱，可导致血管重构和收缩功能异常，进而导致高血压发生；其机制可能与管周脂肪局部脂肪因子和血管活性物质失调、以及脂肪酸氧化过度产生氧化应激损伤等有关。本课题从与血管外膜毗邻的管周脂肪入手，研究管周脂肪功能紊乱对血管重构和收缩舒张功能的直接调节作用及与高血压发生的关系，有助于从新的视角解释肥胖和脂肪营养不良症等脂肪功能紊乱性疾病发生高血压的复杂病理生理机制。.Plin1-/-小鼠脂肪组织减少，基础脂肪分解增强，使得脂肪酸释放增加。心脏以脂肪酸为主要的供能物质。Plin1 -/-小鼠心脏重量增加，心肌细胞肥大及心肌纤维化，心脏收缩及舒张功能下降。Plin1 -/-小鼠心肌脂肪酸转运体CD36及FATP1蛋白表达增加；体外同位素示踪方法显示心肌线粒体脂肪酸-氧化能力增强，其机制主要与线粒体CPT-1活性增高及线粒体-氧化相关酶蛋白表达上调有关。油红O染色及透射电镜结果显示Plin1 -/-小鼠心肌脂质蓄积。通过酶学方法检测，我们发现其心肌内脂肪酸和甘油三酯含量显著增多，后者主要与甘油三酯合成关键酶DGAT1及DGAT2蛋白表达增高及甘油三酯水解限速酶HSL和ATGL蛋白表达下降相关。Plin1 -/-小鼠心肌脂肪酸氧化代谢增强，ROS产生增多；同时，酶学测定结果显示其心肌过氧化氢酶(CAT)活性及GSH/GSSG比值均显著下降，心肌过氧化脂质产物丙二醛含量增多。Perilipin基因敲除小鼠作为一个新的心肌代谢性肥厚模型，揭示由于脂肪组织脂肪酸代谢异常引起心肌脂质代谢紊乱，最终导致心肌结构异常及功能障碍，有助于加深对代谢性心肌肥厚发生机制的理解。