Genetic Ablation of Transmembrane Prolyl 4-Hydroxylase Reduces Atherosclerotic Plaques in Mice. Issue 7 (27th May 2021)

• Record Type: Journal Article
• Authors: Määttä, Jenni; Serpi, Raisa; Hörkkö, Sohvi; Izzi, Valerio; Myllyharju, Johanna; Dimova, Elitsa Y.; Koivunen, Peppi
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 41:Issue 7(2021)
• Page Start: 2128
• Page End: 2140
• Publication Date: 2021-05-27
• Subjects: atherosclerosis -- cardiovascular diseases -- hypertriglyceridemia -- lipoprotein lipase -- prolyl 4-hydroxylase -- triglycerides; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.121.316034
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : Supplemental Digital Content is available in the text. 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 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.