Vascular Biology Lab, Institute of Experimental Medicine and Biology of Cuyo (IMBECU) CONICET, School of Medical Sciences, National University of Cuyo, Mendoza, Argentina.
Laboratory of Cardiovascular Physiopathology, Institute of Experimental Medicine and Biology of Cuyo (IMBECU) - CONICET, Mendoza, Argentina.
Cardiovasc Ther. 2018 Jun;36(3):e12322. doi: 10.1111/1755-5922.12322. Epub 2018 Mar 7.
Perivascular adipose tissue (PVAT) is in intimate contact with the vessel wall and extravascular PVAT-derived inflammatory mediators may adversely influence atherosclerotic plaque formation and stability through outside-to-inside signaling. We sought to investigate the role of PVAT on the atheroma development in an experimental animal model of metabolic syndrome (MS) associated with oxidative stress and low-grade inflammatory state. We also studied the effect of pioglitazone an insulin sensitizer, on the aortic wall and its surrounding PVAT, considering a bi-directional communication between both layers.
Apolipoprotein E-deficient mice (ApoE ) were fed with standard diet (CD, control diet) or fructose overload (10% w/v) (FD, fructose diet) for 8 weeks and treated with or without pioglitazone the latest 4 weeks.
Biochemical variables show that glycemia and lipid peroxidation determined by thiobarbituric acid reactive species (TBARS) significantly increased in FD-fed ApoE mice. FD significantly increased aortic PVAT expression of oxidative stress associated genes: p22 , Nox1, Nox2, Nox4 and p47 , and proinflammatory genes: Visfatin, MCP-1, and MMP-9. Pioglitazone diminished PVAT-oxidative damage elicited by fructose treatment and markedly down-regulated proinflammatory markers. Even pioglitazone did not prevent the development of the aortic atheroma plaques stimulated by FD, significantly diminished VCAM-1 expression, MMP-9 expression and activity in aortic media wall and significantly reduced the accumulation of lipids and macrophages in atheroma plaques.
Our results support the fact that PVAT contributes to the development and progression of cardiovascular disease by underlying mechanisms elicited by "outside-in" signaling. Treatment with pioglitazone may offer a new effect on the whole vessel wall, promoting the stability of advanced atherosclerotic plaques.
血管周围脂肪组织（PVAT）与血管壁紧密接触，血管外 PVAT 衍生的炎症介质可能通过外向内信号影响动脉粥样硬化斑块的形成和稳定性。我们旨在研究代谢综合征（MS）相关氧化应激和低度炎症状态的实验动物模型中，PVAT 在动脉粥样硬化发展中的作用。我们还研究了胰岛素增敏剂吡格列酮对主动脉壁及其周围 PVAT 的影响，考虑到这两层之间的双向通讯。
载脂蛋白 E 缺陷小鼠（ApoE ）喂食标准饮食（CD，对照饮食）或果糖过载（10% w/v）（FD，果糖饮食）8 周，并在最后 4 周用或不用吡格列酮治疗。
生化变量表明，FD 喂养的 ApoE 小鼠的血糖和脂质过氧化产物丙二醛（TBARS）显著增加。FD 显著增加了主动脉 PVAT 氧化应激相关基因的表达：p22 、Nox1、Nox2、Nox4 和 p47 ，以及促炎基因：Visfatin、MCP-1 和 MMP-9。吡格列酮减轻了果糖处理引起的 PVAT 氧化损伤，并显著下调了促炎标志物。即使吡格列酮不能预防 FD 刺激的主动脉粥样斑块的形成，也显著降低了 VCAM-1 表达、MMP-9 表达和活性以及主动脉中层壁的脂质和巨噬细胞的积累。
我们的结果支持这样一个事实，即通过“外向内”信号引发的潜在机制，PVAT 有助于心血管疾病的发展和进展。吡格列酮的治疗可能对整个血管壁提供新的效果，促进晚期动脉粥样硬化斑块的稳定性。
