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

Dimitra Aravani; Gavin E Morris; Peter D Jones; Helena K Tattersall; Elisavet Karamanavi; Michael A Kaiser; Renata B Kostogrys; Maryam Ghaderi Najafabadi; Sarah L Andrews; Mintu Nath; Shu Ye; Emma J Stringer; Nilesh J Samani; Tom R Webb

doi:10.1161/CIRCULATIONAHA.119.041059

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

Dimitra Aravani, Gavin E Morris, Peter D Jones, Helena K Tattersall, Elisavet Karamanavi, Michael A Kaiser, Renata B Kostogrys, Maryam Ghaderi Najafabadi, Sarah L Andrews, Mintu Nath, Shu Ye, Emma J Stringer, Nilesh J Samani, Tom R Webb^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND: Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterised gene called Hedgehog Interacting Protein Like 1 (HHIPL1), which encodes a sequence homologue of an antagonist of hedgehog signaling. The function of HHIPL1 and its role in atherosclerosis is 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-/- mice. Human aortic smooth muscle cell phenotypes and hedgehog signaling were investigated following 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-/- knockout strains and the extent of atherosclerosis was quantified following 12 weeks of high fat diet. Cellular composition and collagen content of aortic plaques was 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 was 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 more than 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.

Original language	English
Pages (from-to)	500–513
Number of pages	14
Journal	Circulation
Volume	140
Issue number	6
Early online date	5 Jun 2019
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.119.041059
Publication status	Published - 6 Aug 2019

Bibliographical note

The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007–2013 under grant agreement number HEALTH-F2-2013–601456, a Transatlantic Networks of Excellence Award (12CVD02) from The Leducq Foundation and the British Heart Foundation (SP/18/8/33620) as a partner of the European Research Area Network on Cardiovascular Diseases (ERA-CVD) druggable-MI-genes (01KL1802) and supported by the UK National Institute for Health Research (NIHR) Leicester Biomedical Research Centre. Dr Samani is a UK NIHR Senior Investigator. Drs Morris, Ye, and Webb are funded by the British Heart Foundation (SP/16/4/32697).

Keywords

atherosclerosis
coronary artery disease
genome-wide association study
hedgehogs
signaling
MIGRATION
ACTIVATION
VESSEL
PROTEIN
ANGIOGENESIS
SONIC HEDGEHOG
MUSCLE-CELL PROLIFERATION
INDUCTION
PATHWAY
EXPRESSION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Aravani_et_al_Circ_HH1PL1
© 2019 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Final published version, 1.31 MBLicence: CC BY

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Cite this

Aravani, D., Morris, G. E., Jones, P. D., Tattersall, H. K., Karamanavi, E., Kaiser, M. A., Kostogrys, R. B., Ghaderi Najafabadi, M., Andrews, S. L., Nath, M., Ye, S., Stringer, E. J., Samani, N. J., & Webb, T. R. (2019). HHIPL1, a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis. Circulation, 140(6), 500–513. https://doi.org/10.1161/CIRCULATIONAHA.119.041059

Aravani, D, Morris, GE, Jones, PD, Tattersall, HK, Karamanavi, E, Kaiser, MA, Kostogrys, RB, Ghaderi Najafabadi, M, Andrews, SL, Nath, M, Ye, S, Stringer, EJ, Samani, NJ & Webb, TR 2019, 'HHIPL1, a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis', Circulation, vol. 140, no. 6, pp. 500–513. https://doi.org/10.1161/CIRCULATIONAHA.119.041059

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

abstract = "BACKGROUND: Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterised gene called Hedgehog Interacting Protein Like 1 (HHIPL1), which encodes a sequence homologue of an antagonist of hedgehog signaling. The function of HHIPL1 and its role in atherosclerosis is 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-/- mice. Human aortic smooth muscle cell phenotypes and hedgehog signaling were investigated following 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-/- knockout strains and the extent of atherosclerosis was quantified following 12 weeks of high fat diet. Cellular composition and collagen content of aortic plaques was 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 was 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 more than 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.",

keywords = "atherosclerosis, coronary artery disease, genome-wide association study, hedgehogs, signaling, MIGRATION, ACTIVATION, VESSEL, PROTEIN, ANGIOGENESIS, SONIC HEDGEHOG, MUSCLE-CELL PROLIFERATION, INDUCTION, PATHWAY, EXPRESSION",

author = "Dimitra Aravani and Morris, {Gavin E} and Jones, {Peter D} and Tattersall, {Helena K} and Elisavet Karamanavi and Kaiser, {Michael A} and Kostogrys, {Renata B} and {Ghaderi Najafabadi}, Maryam and Andrews, {Sarah L} and Mintu Nath and Shu Ye and Stringer, {Emma J} and Samani, {Nilesh J} and Webb, {Tom R}",

note = "The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007–2013 under grant agreement number HEALTH-F2-2013–601456, a Transatlantic Networks of Excellence Award (12CVD02) from The Leducq Foundation and the British Heart Foundation (SP/18/8/33620) as a partner of the European Research Area Network on Cardiovascular Diseases (ERA-CVD) druggable-MI-genes (01KL1802) and supported by the UK National Institute for Health Research (NIHR) Leicester Biomedical Research Centre. Dr Samani is a UK NIHR Senior Investigator. Drs Morris, Ye, and Webb are funded by the British Heart Foundation (SP/16/4/32697).",

year = "2019",

month = aug,

day = "6",

doi = "10.1161/CIRCULATIONAHA.119.041059",

language = "English",

volume = "140",

pages = "500–513",

journal = "Circulation",

issn = "0009-7322",

publisher = "American Heart Association",

number = "6",

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TY - JOUR

T1 - HHIPL1, a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis

AU - Aravani, Dimitra

AU - Morris, Gavin E

AU - Jones, Peter D

AU - Tattersall, Helena K

AU - Karamanavi, Elisavet

AU - Kaiser, Michael A

AU - Kostogrys, Renata B

AU - Ghaderi Najafabadi, Maryam

AU - Andrews, Sarah L

AU - Nath, Mintu

AU - Ye, Shu

AU - Stringer, Emma J

AU - Samani, Nilesh J

AU - Webb, Tom R

N1 - The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007–2013 under grant agreement number HEALTH-F2-2013–601456, a Transatlantic Networks of Excellence Award (12CVD02) from The Leducq Foundation and the British Heart Foundation (SP/18/8/33620) as a partner of the European Research Area Network on Cardiovascular Diseases (ERA-CVD) druggable-MI-genes (01KL1802) and supported by the UK National Institute for Health Research (NIHR) Leicester Biomedical Research Centre. Dr Samani is a UK NIHR Senior Investigator. Drs Morris, Ye, and Webb are funded by the British Heart Foundation (SP/16/4/32697).

PY - 2019/8/6

Y1 - 2019/8/6

N2 - BACKGROUND: Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterised gene called Hedgehog Interacting Protein Like 1 (HHIPL1), which encodes a sequence homologue of an antagonist of hedgehog signaling. The function of HHIPL1 and its role in atherosclerosis is 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-/- mice. Human aortic smooth muscle cell phenotypes and hedgehog signaling were investigated following 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-/- knockout strains and the extent of atherosclerosis was quantified following 12 weeks of high fat diet. Cellular composition and collagen content of aortic plaques was 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 was 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 more than 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.

AB - BACKGROUND: Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterised gene called Hedgehog Interacting Protein Like 1 (HHIPL1), which encodes a sequence homologue of an antagonist of hedgehog signaling. The function of HHIPL1 and its role in atherosclerosis is 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-/- mice. Human aortic smooth muscle cell phenotypes and hedgehog signaling were investigated following 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-/- knockout strains and the extent of atherosclerosis was quantified following 12 weeks of high fat diet. Cellular composition and collagen content of aortic plaques was 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 was 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 more than 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.

KW - atherosclerosis

KW - coronary artery disease

KW - genome-wide association study

KW - hedgehogs

KW - signaling

KW - MIGRATION

KW - ACTIVATION

KW - VESSEL

KW - PROTEIN

KW - ANGIOGENESIS

KW - SONIC HEDGEHOG

KW - MUSCLE-CELL PROLIFERATION

KW - INDUCTION

KW - PATHWAY

KW - EXPRESSION

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

Abstract

Bibliographical note

Keywords

UN SDGs

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Mintu Nath

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

Abstract

Bibliographical note

Keywords

UN SDGs

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Mintu Nath

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