Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice

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Ruotsalainen , A-K , Lappalainen , J P , Heiskanen , E , Merentie , M , Sihvola , V , Näpänkangas , J , Lottonen-Raikaslehto , L , Kansanen , E , Adinolfi , S , Kaarniranta , K , Ylä-Herttuala , S , Jauhiainen , M , Pirinen , E & Levonen , A-L 2019 , ' Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice ' , Cardiovascular Research , vol. 115 , no. 1 , pp. 243-254 . https://doi.org/10.1093/cvr/cvy143

Title: Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice
Author: Ruotsalainen, Anna-Kaisa; Lappalainen, Jari P.; Heiskanen, Emmi; Merentie, Mari; Sihvola, Virve; Näpänkangas, Juha; Lottonen-Raikaslehto, Line; Kansanen, Emilia; Adinolfi, Simone; Kaarniranta, Kai; Ylä-Herttuala, Seppo; Jauhiainen, Matti; Pirinen, Eija; Levonen, Anna-Liisa
Contributor: University of Helsinki, Department of Biochemistry and Developmental Biology
Date: 2019-01-01
Language: eng
Number of pages: 12
Belongs to series: Cardiovascular Research
ISSN: 0008-6363
URI: http://hdl.handle.net/10138/311312
Abstract: Aims Oxidative stress and inflammation play an important role in the progression of atherosclerosis. Transcription factor NF-E2-related factor 2 (Nrf2) has antioxidant and anti-inflammatory effects in the vessel wall, but paradoxically, global loss of Nrf2 in apoE deficient mice alleviates atherosclerosis. In this study, we investigated the effect of global Nrf2 deficiency on early and advanced atherogenesis in alternative models of atherosclerosis, LDL receptor deficient mice (LDLR-/-), and LDLR-/- mice expressing apoB-100 only (LDLR-/- ApoB(100/100)) having a humanized lipoprotein profile. Methods and results LDLR-/- mice were fed a high-fat diet (HFD) for 6 or 12weeks and LDLR(-/-)ApoB(100/100) mice a regular chow diet for 6 or 12months. Nrf2 deficiency significantly reduced early and more advanced atherosclerosis assessed by lesion size and coverage in the aorta in both models. Nrf2 deficiency in LDLR-/- mice reduced total plasma cholesterol after 6weeks of HFD and triglycerides in LDLR(-/-)ApoB(100/100) mice on a chow diet. Nrf2 deficiency aggravated aortic plaque maturation in aged LDLR(-/-)ApoB(100/100) mice as it increased plaque calcification. Moreover, approximate to 36% of Nrf2(-/-)LDLR(-/-)ApoB(100/100) females developed spontaneous myocardial infarction (MI) or sudden death at 5 to 12months of age. Interestingly, Nrf2 deficiency increased plaque instability index, enhanced plaque inflammation and calcification, and reduced fibrous cap thickness in brachiocephalic arteries of LDLR(-/-)ApoB(100/100) female mice at age of 12months. Conclusions Absence of Nrf2 reduced atherosclerotic lesion size in both atherosclerosis models, likely via systemic effects on lipid metabolism. However, Nrf2 deficiency in aged LDLR(-/-)ApoB(100/100) mice led to an enhanced atherosclerotic plaque instability likely via increased plaque inflammation and oxidative stress, which possibly predisposed to MI and sudden death.
Subject: Nrf2
MONOCYTE CHEMOATTRACTANT PROTEIN-1
LOW-DENSITY-LIPOPROTEIN
APOLIPOPROTEIN-E
CHOLESTEROL TRANSPORT
NRF2
EXPRESSION
GROWTH
DIET
SUSCEPTIBILITY
PROGRESSION
Oxidative stress
Inflammation
Atherosclerosis
Plaque instability
3111 Biomedicine
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