HHIPL1, a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis

被引:31
作者
Aravani, Dimitra [1 ,2 ]
Morris, Gavin E. [1 ,2 ]
Jones, Peter D. [1 ,2 ]
Tattersall, Helena K. [1 ,2 ]
Karamanavi, Elisavet [1 ,2 ]
Kaiser, Michael A. [1 ,2 ]
Kostogrys, Renata B. [3 ]
Ghaderi Najafabadi, Maryam [1 ,2 ]
Andrews, Sarah L. [1 ,2 ]
Nath, Mintu [1 ,2 ]
Ye, Shu [1 ,2 ]
Stringer, Emma J. [1 ,2 ]
Samani, Nilesh J. [1 ,2 ]
Webb, Tom R. [1 ,2 ]
机构
[1] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England
[2] Glenfield Hosp, Natl Inst Hlth Res Leicester Biomed Res Ctr, Leicester, Leics, England
[3] Univ Agr, Dept Human Nutr, Fac Food Technol, Krakow, Poland
关键词
atherosclerosis; coronary artery disease; genome-wide association study; hedgehogs; signaling; MUSCLE-CELL PROLIFERATION; SONIC HEDGEHOG; PATHWAY; MIGRATION; ANGIOGENESIS; ACTIVATION; EXPRESSION; INDUCTION; PROTEIN; VESSEL;
D O I
10.1161/CIRCULATIONAHA.119.041059
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease. The disease-associated variants fall in a hitherto uncharacterized gene called HHIPL1 (hedgehog interacting protein-like 1), which encodes a sequence homolog of an antagonist of hedgehog signaling. The function of HHIPL1 and its role in atherosclerosis are unknown. Methods: HHIPL1 cellular localization, interaction with sonic hedgehog (SHH), and influence on hedgehog signaling were tested. HHIPL1 expression was measured in coronary artery disease-relevant human cells, and protein localization was assessed in wild-type and Apoe(-/-) (apolipoprotein E deficient) mice. Human aortic smooth muscle cell phenotypes and hedgehog signaling were investigated after gene knockdown. Hhipl1(-/-) mice were generated and aortic smooth muscle cells collected for phenotypic analysis and assessment of hedgehog signaling activity. Hhipl1(-/-) mice were bred onto both the Apoe(-/-) and Ldlr(-/-) (low-density lipoprotein receptor deficient) knockout strains, and the extent of atherosclerosis was quantified after 12 weeks of high-fat diet. Cellular composition and collagen content of aortic plaques were assessed by immunohistochemistry. Results: In vitro analyses revealed that HHIPL1 is a secreted protein that interacts with SHH and increases hedgehog signaling activity. HHIPL1 expression was detected in human smooth muscle cells and in smooth muscle within atherosclerotic plaques of Apoe(-/-) mice. The expression of Hhipl1 increased with disease progression in aortic roots of Apoe(-/-) mice. Proliferation and migration were reduced in Hhipl1 knockout mouse and HHIPL1 knockdown aortic smooth muscle cells, and hedgehog signaling was decreased in HHIPL1-deficient cells. Hhipl1 knockout caused a reduction of >50% in atherosclerosis burden on both Apoe(-/-) and Ldlr(-/-) knockout backgrounds, and lesions were characterized by reduced smooth muscle cell content. Conclusions: HHIPL1 is a secreted proatherogenic protein that enhances hedgehog signaling and regulates smooth muscle cell proliferation and migration. Inhibition of HHIPL1 protein function might offer a novel therapeutic strategy for coronary artery disease.
引用
收藏
页码:500 / 513
页数:14
相关论文
共 50 条
[1]   The Hedgehog Signalling Pathway in Cell Migration and Guidance: What We Have Learned from Drosophila melanogaster [J].
Araujo, Sofia J. .
CANCERS, 2015, 7 (04) :2012-2022
[2]   Disruption of hedgehog signalling in ApoE-/- mice reduces plasma lipid levels, but increases atherosclerosis due to enhanced lipid uptake by macrophages [J].
Beckers, L. ;
Heeneman, S. ;
Wang, L. ;
Burkly, L. C. ;
Rousch, M. M. J. ;
Davidson, N. O. ;
Gijbels, M. J. J. ;
de Winther, M. P. J. ;
Daemen, M. J. A. P. ;
Lutgens, E. .
JOURNAL OF PATHOLOGY, 2007, 212 (04) :420-428
[3]   The mechanisms of Hedgehog signalling and its roles in development and disease [J].
Briscoe, James ;
Therond, Pascal P. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2013, 14 (07) :416-429
[4]  
Byrd N, 2002, DEVELOPMENT, V129, P361
[5]   Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein [J].
Chuang, PT ;
McMahon, AP .
NATURE, 1999, 397 (6720) :617-621
[6]   Feedback control of mammalian hedgehog signaling by the hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung [J].
Chuang, PT ;
Kawcak, T ;
McMahon, AP .
GENES & DEVELOPMENT, 2003, 17 (03) :342-347
[7]   Hedgehog regulates distinct vascular patterning events through VEGF-dependent and -independent mechanisms [J].
Coultas, Leigh ;
Nieuwenhuis, Erica ;
Anderson, Gregory A. ;
Cabezas, Jorge ;
Nagy, Andras ;
Henkelman, R. Mark ;
Hui, Chi-Chung ;
Rossant, Janet .
BLOOD, 2010, 116 (04) :653-660
[8]  
Dyer MA, 2001, DEVELOPMENT, V128, P1717
[9]   Sonic hedgehog protein promotes bone marrow-derived endothelial progenitor cell proliferation, migration and VEGF production via Pl 3-kinase/Akt signaling pathways [J].
Fu, Jin-Rong ;
Liu, Wen-Li ;
Zhou, Jian-Feng ;
Sun, Han-Ying ;
Xu, Hui-Zhen ;
Luo, Li ;
Zhang, Heng ;
Zhou, Yu-Feng .
ACTA PHARMACOLOGICA SINICA, 2006, 27 (06) :685-693
[10]   Crystal structure of a scavenger receptor cysteine-rich domain sheds light on an ancient superfamily [J].
Hohenester, E ;
Sasaki, T ;
Timpl, R .
NATURE STRUCTURAL BIOLOGY, 1999, 6 (03) :228-232