Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury

• Published in: Journal of molecular and cellular cardiology 2013-04, Vol.57, p.1-12
• Main Authors: Tian, Zhe, Miyata, Keishi, Tazume, Hirokazu, Sakaguchi, Hisashi, Kadomatsu, Tsuyoshi, Horio, Eiji, Takahashi, Otowa, Komohara, Yoshihiro, Araki, Kimi, Hirata, Yoichiro, Tabata, Minoru, Takanashi, Shuichiro, Takeya, Motohiro, Hao, Hiroyuki, Shimabukuro, Michio, Sata, Masataka, Kawasuji, Michio, Oike, Yuichi
• Format: Article
• Language: English
• Subjects: Adiponectin; Adiponectin - metabolism; Adipose Tissue - metabolism; Adipose Tissue - secretion; Adolescent; Adult; Aged; Aged, 80 and over; Angiopoietin-like Proteins; Angiopoietins - genetics; Angiopoietins - metabolism; Angiopoietins - secretion; Angptl2; Animals; Cardiovascular; Child; Coronary Artery Disease - metabolism; Coronary Artery Disease - pathology; Coronary Vessels - metabolism; Cytokines - genetics; Cytokines - metabolism; Endovascular injury; Female; Femoral Artery - metabolism; Femoral Artery - pathology; Gene Expression; Humans; Hypercholesterolemia - metabolism; Hypercholesterolemia - pathology; Hyperplasia; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Neointima - metabolism; Neointima - pathology; Perivascular adipose tissue; Pro-inflammation; Transcriptional Activation; Vascular System Injuries - metabolism; Vascular System Injuries - pathology
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2013.01.004

Abstract Much attention is currently focused on the role of perivascular adipose tissue in development of cardiovascular disease (CVD). Some researchers view it as promoting CVD through secretion of cytokines and growth factors called adipokines, while recent reports reveal that perivascular adipose tissue can exert a protective effect on CVD development. Furthermore, adiponectin, an anti-inflammatory adipokine, reportedly suppresses neointimal hyperplasia after endovascular injury, whereas such vascular remodeling is enhanced by pro-inflammatory adipokines secreted by perivascular adipose, such as tumor necrosis factor-α (TNF-α). These findings suggest that extent of vascular remodeling, a pathological process associated with CVD development, depends on the balance between pro- and anti-inflammatory adipokines secreted from perivascular adipose tissue. We previously demonstrated that angiopoietin-like protein 2 (Angptl2), a pro-inflammatory factor secreted by adipose tissue, promotes adipose tissue inflammation and subsequent systemic insulin resistance in obesity. Here, we examined whether Angptl2 secreted by perivascular adipose tissue contributes to vascular remodeling after endovascular injury in studies of transgenic mice expressing Angptl2 in adipose tissue ( aP2-Angptl2 transgenic mice) and Angptl2 knockout mice ( Angptl2 − / − mice). To assess the role of Angptl2 secreted by perivascular adipose tissue on vascular remodeling after endovascular injury, we performed adipose tissue transplantation experiments using these mice. Wild-type mice with perivascular adipose tissue derived from aP2-Angptl2 mice exhibited accelerated neointimal hyperplasia after endovascular injury compared to wild-type mice transplanted with wild-type tissue. Conversely, vascular inflammation and neointimal hyperplasia after endovascular injury were significantly attenuated in wild-type mice transplanted with Angptl2 − / − mouse-derived perivascular adipose tissue compared to wild-type mice transplanted with wild-type tissue. RT-PCR analysis revealed that mouse Angptl2 expression in perivascular adipose tissue was significantly increased by aging, hypercholesterolemia, and endovascular injury, all risk factors for coronary heart disease (CHD). Immunohistochemical and RT-PCR analysis of tissues from patients with CHD and from non-CHD patients indicated that ANGPTL2 expression in epicardial adipose tissue was unchanged. Interestingly, that analysis also revealed a positive cor