Genetic ablation of P4H-TM (transmembrane prolyl 4-hydroxylase) reduces atherosclerotic plaques in mice
Määttä, Jenni; Serpi, Raisa; Hörkkö, Sohvi; Izzi, Valerio; Myllyharju, Johanna; Dimova, Elitsa Y.; Koivunen, Peppi (2021-05-27)
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
© 2021 American Heart Association, Inc. The final authenticated version is available online at https://doi.org/10.1161/atvbaha.121.316034.
https://rightsstatements.org/vocab/InC/1.0/
https://urn.fi/URN:NBN:fi-fe2021060132653
Tiivistelmä
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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