Differences between perivascular adipose tissue surrounding the heart and the internal mammary artery: possible role for the leptin-inflammation-fibrosis-hypoxia axis
Differences between perivascular adipose tissue surrounding the heart and the internal mammary artery: possible role for the leptin-inflammation-fibrosis-hypoxia axis
复制标题
DOI：
10.1007/s00392-016-0996-7
复制
发表时间：
2016-11-01
影响因子：
5
通讯作者：
Schaefer, Katrin
中科院分区：
文献类型：
--
作者：
Drosos, Ioannis;Chalikias, Georgios;Schaefer, Katrin
血管周围脂肪组织(PVAT)在动脉粥样硬化中发挥旁分泌作用的因素目前尚不清楚。脂肪因子瘦素与肥胖心血管风险增加有关，并可能局部促进新生内膜的形成，而不依赖于循环中的瘦素水平。在已确诊的冠状动脉疾病患者中，我们检测了瘦素及其可能的诱导物在主动脉根部和冠状动脉周围的心脏PVAT(C-PVAT)中的表达，并与抗动脉粥样硬化的乳内动脉PVAT(IMA-PVAT)进行了比较。与IMA-PVAT相比，C-PVAT的瘦素蛋白表达增加，与血清瘦素水平无关。与IMA-PVAT相比，C-PVAT表现出更明显的血管生成和炎症，表现为PECAM1阳性血管和CD68阳性巨噬细胞的数量显著增加，并且具有更大的纤维化和缺氧程度。在C-PVAT中观察到低氧诱导因子-1α和Fos-like抗原(FOSL)2的表达增加，这两种已知的促进瘦素基因转录的因子。作为概念的证明，人类脂肪细胞暴露于化学缺氧导致FOSL2和瘦素mRNA水平显著增加。局部组织缺氧程度更高，血管周围脂肪组织中瘦素表达上调，以及血管化、炎症和纤维化增加，可能是导致冠状动脉中动脉粥样硬化斑块负担增加的原因。
The factors mediating the paracrine effects of perivascular adipose tissue (PVAT) in atherosclerosis are largely unknown. The adipokine leptin has been implicated in the increased cardiovascular risk in obesity and may locally promote neointima formation independently of circulating leptin levels. In patients with established coronary artery disease, we examined the expression of leptin as well as of its possible inducers in 'cardiac' PVAT surrounding the aortic root and coronary arteries (C-PVAT), and compared it to the PVAT surrounding the internal mammary artery (IMA-PVAT), a vessel resistant to atherosclerosis.Tissue specimens collected from male patients undergoing coronary artery bypass surgery were processed for real-time PCR, ELISA, in situ hybridization, and immunohistochemistry analysis. Leptin protein expression was elevated in C-PVAT compared to IMA-PVAT, independent of serum leptin levels. Compared to IMA-PVAT, C-PVAT exhibited more pronounced angiogenesis and inflammation, as indicated by significantly higher numbers of PECAM1-positive vessels and CD68-positive macrophages, and was characterized by a greater extent of fibrosis and hypoxia. Increased expression of hypoxia-inducible factor-1 alpha and Fos-like antigen (FOSL)2, factors known to enhance leptin gene transcription, was observed in C-PVAT. As a proof of concept, exposure of human adipocytes to chemical hypoxia resulted in significantly increased FOSL2 and leptin mRNA levels.A higher degree of local tissue hypoxia and up-regulation of leptin expression in the perivascular adipose tissue, along with increased vascularization, inflammation, and fibrosis, may contribute to the increased atherosclerotic plaque burden in the coronary arteries compared to the IMA.