Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 41, Issue 7, Pages 2128-2140Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.121.316034
Keywords
atherosclerosis; cardiovascular diseases; hypertriglyceridemia; lipoprotein lipase; prolyl 4-hydroxylase; triglycerides
Categories
Funding
- Academy of Finland [266719, 308009, 296498]
- Academy of Finland Centre of Excellence Grant [251314]
- S. Juselius Foundation
- Jane and Aatos Erkko Foundation
- FibroGen Inc
- Finnish Cancer Organizations
- Academy of Finland (AKA) [266719, 296498] Funding Source: Academy of Finland (AKA)
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The genetic ablation of P4H-TM was shown to protect against atherosclerosis by potentially modulating immuno-metabolic interactions, including the presence of IgM antibodies to Ox-LDL and increased lipoprotein lipase levels. This mechanism could provide a novel approach for intervention in atherosclerosis pathology by targeting hypertriglyceridemia and promoting protective immune responses.
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 LPL (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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