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

Anna-Kaisa Ruotsalainen, Jari P. Lappalainen, Emmi Heiskanen, Mari Merentie, Virve Sihvola, Juha Näpänkangas, Line Lottonen-Raikaslehto, Emilia Kansanen, Simone Adinolfi, Kai Kaarniranta, Seppo Ylä-Herttuala, Matti Jauhiainen, Eija Pirinen, Anna-Liisa Levonen

Research output: Contribution to journalArticleScientificpeer-review

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.

Original languageEnglish
JournalCardiovascular Research
Volume115
Issue number1
Pages (from-to)243-254
Number of pages12
ISSN0008-6363
DOIs
Publication statusPublished - 1 Jan 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 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

Cite this

Ruotsalainen, A-K., Lappalainen, J. P., Heiskanen, E., Merentie, M., Sihvola, V., Näpänkangas, J., ... 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, 115(1), 243-254. https://doi.org/10.1093/cvr/cvy143
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. / Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice. In: Cardiovascular Research. 2019 ; Vol. 115, No. 1. pp. 243-254.
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title = "Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice",
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.",
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author = "Anna-Kaisa Ruotsalainen and Lappalainen, {Jari P.} and Emmi Heiskanen and Mari Merentie and Virve Sihvola and Juha N{\"a}p{\"a}nkangas and Line Lottonen-Raikaslehto and Emilia Kansanen and Simone Adinolfi and Kai Kaarniranta and Seppo Yl{\"a}-Herttuala and Matti Jauhiainen and Eija Pirinen and Anna-Liisa Levonen",
year = "2019",
month = "1",
day = "1",
doi = "10.1093/cvr/cvy143",
language = "English",
volume = "115",
pages = "243--254",
journal = "Cardiovascular Research",
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publisher = "Oxford University Press",
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Ruotsalainen, A-K, Lappalainen, JP, 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

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

In: Cardiovascular Research, Vol. 115, No. 1, 01.01.2019, p. 243-254.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice

AU - Ruotsalainen, Anna-Kaisa

AU - Lappalainen, Jari P.

AU - Heiskanen, Emmi

AU - Merentie, Mari

AU - Sihvola, Virve

AU - Näpänkangas, Juha

AU - Lottonen-Raikaslehto, Line

AU - Kansanen, Emilia

AU - Adinolfi, Simone

AU - Kaarniranta, Kai

AU - Ylä-Herttuala, Seppo

AU - Jauhiainen, Matti

AU - Pirinen, Eija

AU - Levonen, Anna-Liisa

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Nrf2

KW - MONOCYTE CHEMOATTRACTANT PROTEIN-1

KW - LOW-DENSITY-LIPOPROTEIN

KW - APOLIPOPROTEIN-E

KW - CHOLESTEROL TRANSPORT

KW - NRF2

KW - EXPRESSION

KW - GROWTH

KW - DIET

KW - SUSCEPTIBILITY

KW - PROGRESSION

KW - Oxidative stress

KW - Inflammation

KW - Atherosclerosis

KW - Plaque instability

KW - 3111 Biomedicine

U2 - 10.1093/cvr/cvy143

DO - 10.1093/cvr/cvy143

M3 - Article

VL - 115

SP - 243

EP - 254

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 1

ER -