Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia

Zihan Ma^#^{1

2}, Chenfeng Mao^#^{1

2

3}, Xiao Chen^{4

5}, Shiyu Yang^{1

2}, Zhihua Qiu^{4

5}, Baoqi Yu^{6

7}, Yiting Jia^{1

2}, Chao Wu⁸, Yiyi Wang^{4

5}, Yuhui Wang⁹, Rui Gu^{1

2}, Fang Yu^{1

2}, Yanhui Yin^{10

11}, Xian Wang^{1

2}, Qingbo Xu^{12

13}, Chuanju Liu¹⁴, Yuhua Liao^{4

5}, Jingang Zheng⁸, Yi Fu^{1

2}, Wei Kong^{1

2}

Affiliations

¹ Department of Physiology and Pathophysiology (Z.M., C.M., S.Y., Y.J., R.G., F.Y., X.W., Y.F., W.K.), Peking University, Beijing, China.
² Key Laboratory of Molecular Cardiovascular Science (Z.M., C.M., S.Y., Y.J., R.G., F.Y., X.W., Y.F., W.K.), Ministry of Education, Beijing, China.
³ Beijing Institute of Biotechnology, Beijing, China (C.M.).
⁴ Department of Cardiology and Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.C., Z.Q., Yiyi Wang, Y.L.).
⁵ Key Laboratory of Molecular Biological Targeted Therapies, Ministry of Education, Wuhan, China (X.C., Z.Q., Yiyi Wang, Y.L.).
⁶ Key Laboratory of Remodeling-Related Cardiovascular Diseases (B.Y.), Ministry of Education, Beijing, China.
⁷ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China (B.Y.).
⁸ Department of Cardiology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China (C.W., J.Z.).
⁹ School of Basic Medical Sciences, Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education (Yuhui Wang), Peking University, Beijing, China.
¹⁰ Department of Immunology (Y.Y.), Peking University, Beijing, China.
¹¹ Key Laboratory of Medical Immunology of Ministry of Health (Y.Y.), Peking University, Beijing, China.
¹² School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, United Kingdom (Q.X.).
¹³ Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (Q.X.).
¹⁴ Department of Orthopedic Surgery, Department of Cell Biology, New York University School of Medicine, New York, NY (C.L.).

^# Contributed equally.

PMID: 36562301
DOI: 10.1161/CIRCULATIONAHA.122.061516

Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia

Zihan Ma et al. Circulation. 2023.

. 2023 Feb 28;147(9):728-742.

doi: 10.1161/CIRCULATIONAHA.122.061516. Epub 2022 Dec 23.

Authors

Affiliations

¹ Department of Physiology and Pathophysiology (Z.M., C.M., S.Y., Y.J., R.G., F.Y., X.W., Y.F., W.K.), Peking University, Beijing, China.
² Key Laboratory of Molecular Cardiovascular Science (Z.M., C.M., S.Y., Y.J., R.G., F.Y., X.W., Y.F., W.K.), Ministry of Education, Beijing, China.
³ Beijing Institute of Biotechnology, Beijing, China (C.M.).
⁴ Department of Cardiology and Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.C., Z.Q., Yiyi Wang, Y.L.).
⁵ Key Laboratory of Molecular Biological Targeted Therapies, Ministry of Education, Wuhan, China (X.C., Z.Q., Yiyi Wang, Y.L.).
⁶ Key Laboratory of Remodeling-Related Cardiovascular Diseases (B.Y.), Ministry of Education, Beijing, China.
⁷ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China (B.Y.).
⁸ Department of Cardiology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China (C.W., J.Z.).
⁹ School of Basic Medical Sciences, Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education (Yuhui Wang), Peking University, Beijing, China.
¹⁰ Department of Immunology (Y.Y.), Peking University, Beijing, China.
¹¹ Key Laboratory of Medical Immunology of Ministry of Health (Y.Y.), Peking University, Beijing, China.
¹² School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, United Kingdom (Q.X.).
¹³ Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (Q.X.).
¹⁴ Department of Orthopedic Surgery, Department of Cell Biology, New York University School of Medicine, New York, NY (C.L.).

^# Contributed equally.

PMID: 36562301
DOI: 10.1161/CIRCULATIONAHA.122.061516

Abstract

Background: The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents.

Methods: We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant. Arterial ligation or wire injury was used to induce neointima in mice, whereas ApoE^-/- and LDLR^-/- (LDLR [low-density lipoprotein receptor]) mice fed a high-fat diet were applied to assess atherosclerosis. In addition, coronary stent implantation was performed on vaccine-immunized Bama miniature pigs, followed by optical coherence tomography to evaluate coronary intimal hyperplasia.

Results: A vaccine, ATS7vac, was screened out from 3 candidates to effectively inhibit intimal thickening in murine carotid artery ligation models after vaccination. As well, immunization with ATS7vac alleviated neointima formation in murine wire injury models and mitigated atherosclerotic lesions in both hyperlipidemic ApoE^-/- and LDLR^-/- mice without lowering lipid levels. Preclinically, ATS7vac markedly impeded intimal hyperplasia in swine stented coronary arteries, but without significant immune-related organ injuries. Mechanistically, ATS7vac vaccination produced specific antibodies against ADAMTS-7, which markedly repressed ADAMTS-7-mediated COMP (cartilage oligomeric matrix protein) and TSP-1 (thrombospondin-1) degradation and subsequently inhibited vascular smooth muscle cell migration but promoted re-endothelialization.

Conclusions: ATS7vac is a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac would be a complementary therapeutic avenue to the current lipid-lowering strategy for atherosclerotic disease.

Keywords: ADAMTS-7; atherosclerosis; in-stent restenosis; therapeutic vaccine.

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Comment in

Targeting ADAMTS-7: A Vaccination Against Atherosclerosis-and Its Complications?
Kessler T, Schunkert H. Kessler T, et al. Circulation. 2023 Feb 28;147(9):743-745. doi: 10.1161/CIRCULATIONAHA.122.063495. Epub 2023 Feb 27. Circulation. 2023. PMID: 36848412 Free PMC article. No abstract available.

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Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia

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Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia

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