University of Oulu

Määttä, J., Serpi, R., Hörkkö, S., Izzi, V., Myllyharju, J., Dimova, E. Y., & Koivunen, P. (2021). Genetic Ablation of Transmembrane Prolyl 4-Hydroxylase Reduces Atherosclerotic Plaques in Mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 41(7), 2128–2140. https://doi.org/10.1161/atvbaha.121.316034

Genetic ablation of P4H-TM (transmembrane prolyl 4-hydroxylase) reduces atherosclerotic plaques in mice

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Author: Määttä, Jenni1; Serpi, Raisa1; Hörkkö, Sohvi2;
Organizations: 1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Finland
2Institute of Biomedicine, University of Oulu, Finland
3Faculty of Medicine, University of Oulu, Finland
4Finnish Cancer Institute, Helsinki, Finland
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2021060132653
Language: English
Published: Wolters Kluwer, 2021
Publish Date: 2021-11-27
Description:

Abstract

Objective: Atherosclerosis is a key component of cardiovascular diseases. We set out to study here whether genetic ablation of P4H-TM (transmembrane prolyl 4-hydroxylase) could protect against atherosclerosis as does inhibition of the other 3 classical HIF-P4Hs (hypoxia-inducible factor prolyl 4-hydroxylases).

Approach and Results: We generated a double knockout mouse line deficient in P4H-TM and LDL (low-density lipoprotein) receptor (P4h-tm−/−/Ldlr−/−) and subjected these mice to a high-fat diet for 13 weeks. The double knockout mice had less atherosclerotic plaques in their full-length aorta than their P4h-tm+/+/Ldlr−/− counterparts and also had lower serum triglyceride levels on standard laboratory diet and high-fat diet, higher levels of IgM autoantibodies against Ox-LDL (oxidized LDL), and significantly higher lipoprotein lipase protein levels in white adipose tissue and sera. RNA-sequencing analysis revealed changes in expression of mRNAs in multiple pathways including lipid metabolism and immunologic response in the P4h-tm−/−/Ldlr−/− livers as compared with P4h-tm+/+/Ldlr−/−.

Conclusions: Our data identify P4H-TM inhibition as a potential novel immuno-metabolic mechanism for intervening in the pathology of atherosclerosis, as hypertriglyceridemia is an individual risk factor for atherosclerosis, and IgM antibodies to Ox-LDL and increased lipoprotein lipase have been associated with protection against it.

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Series: Arteriosclerosis, thrombosis, and vascular biology
ISSN: 1079-5642
ISSN-E: 1524-4636
ISSN-L: 1079-5642
Volume: 41
Pages: 2128 - 2140
DOI: 10.1161/ATVBAHA.121.316034
OADOI: https://oadoi.org/10.1161/ATVBAHA.121.316034
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: This work was supported by Academy of Finland Grants 266719, 308009 (PK) and 296498 (JMy), Academy of Finland Centre of Excellence Grant 251314 (JMy) and grants from the S. Jusélius Foundation (PK and JMy), the Jane and Aatos Erkko Foundation (PK and JMy), the Finnish Cancer Organizations (PK) and FibroGen Inc. (JMy).
Academy of Finland Grant Number: 266719
308009
296498
251314
Detailed Information: 266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
296498 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
Copyright information: © 2021 American Heart Association, Inc. The final authenticated version is available online at https://doi.org/10.1161/atvbaha.121.316034.