PMID- 15210586
OWN - NLM
STAT- MEDLINE
DCOM- 20050110
LR  - 20220310
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 110
IP  - 2
DP  - 2004 Jul 13
TI  - Association of multiple cellular stress pathways with accelerated atherosclerosis 
      in hyperhomocysteinemic apolipoprotein E-deficient mice.
PG  - 207-13
AB  - BACKGROUND: A causal relation between hyperhomocysteinemia (HHcy) and accelerated 
      atherosclerosis has been established in apolipoprotein E-deficient (apoE-/-) 
      mice. Although several cellular stress mechanisms have been proposed to explain 
      the atherogenic effects of HHcy, including oxidative stress, endoplasmic 
      reticulum (ER) stress, and inflammation, their association with atherogenesis has 
      not been completely elucidated. METHODS AND RESULTS: ApoE-/- mice were fed a 
      control or a high-methionine (HM) diet for 4 (early lesion group) or 18 (advanced 
      lesion group) weeks to induce HHcy. Total plasma homocysteine levels and 
      atherosclerotic lesion size were significantly increased in early and advanced 
      lesion groups fed the HM diet compared with control groups. Markers of ER stress 
      (GRP78/94, phospho-PERK), oxidative stress (HSP70), and inflammation 
      (phospho-IkappaB-alpha) were assessed by immunohistochemical staining of these 
      atherosclerotic lesions. GRP78/94, HSP70, and phospho-IkappaB-alpha 
      immunostaining were significantly increased in the advanced lesion group fed the 
      HM diet compared with the control group. HSP47, an ER-resident molecular 
      chaperone involved in collagen folding and secretion, was also increased in 
      advanced lesions of mice fed the HM diet. GRP78/94 and HSP47 were predominantly 
      localized to the smooth muscle cell-rich fibrous cap, whereas HSP70 and 
      phospho-IkappaB-alpha were observed in the lipid-rich necrotic core. Increased 
      HSP70 and phospho-IkappaB-alpha immunostaining in advanced lesions of mice fed 
      the HM diet are consistent with enhanced carotid artery dihydroethidium staining. 
      Interestingly, GRP78/94 and phospho-PERK were markedly increased in macrophage 
      foam cells from early lesions of mice fed the control or the HM diet. 
      CONCLUSIONS: Multiple cellular stress pathways, including ER stress, are 
      associated with atherosclerotic lesion development in apoE-/- mice.
FAU - Zhou, Ji
AU  - Zhou J
AD  - Henderson Research Centre and McMaster University, Hamilton, Ontario, Canada.
FAU - Werstuck, Geoff H
AU  - Werstuck GH
FAU - Lhotak, Sarka
AU  - Lhotak S
FAU - de Koning, A B Lawrence
AU  - de Koning AB
FAU - Sood, Sudesh K
AU  - Sood SK
FAU - Hossain, Gazi S
AU  - Hossain GS
FAU - Moller, Jan
AU  - Moller J
FAU - Ritskes-Hoitinga, Merel
AU  - Ritskes-Hoitinga M
FAU - Falk, Erling
AU  - Falk E
FAU - Dayal, Sanjana
AU  - Dayal S
FAU - Lentz, Steven R
AU  - Lentz SR
FAU - Austin, Richard C
AU  - Austin RC
LA  - eng
GR  - HL-63943/HL/NHLBI NIH HHS/United States
GR  - NS-24621/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040621
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Apolipoproteins E)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (HSP47 Heat-Shock Proteins)
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Hspa5 protein, mouse)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Lipids)
RN  - 0 (Membrane Proteins)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Serpinh1 protein, mouse)
RN  - 0 (Serpins)
RN  - 0 (glucose-regulated proteins)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
SB  - IM
MH  - Animals
MH  - Aortic Diseases/blood/etiology/pathology/physiopathology
MH  - Apolipoproteins E/*deficiency
MH  - Arteriosclerosis/blood/*etiology/pathology/physiopathology
MH  - Carotid Artery Diseases/blood/etiology/pathology
MH  - Collagen/chemistry
MH  - Disease Progression
MH  - Endoplasmic Reticulum/physiology
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Female
MH  - Fibrosis
MH  - Foam Cells/metabolism
MH  - HSP47 Heat-Shock Proteins
MH  - HSP70 Heat-Shock Proteins/physiology
MH  - Heat-Shock Proteins/physiology
MH  - Hypercholesterolemia/etiology
MH  - Hyperhomocysteinemia/chemically induced/*complications/physiopathology
MH  - I-kappa B Proteins/physiology
MH  - Lipids/blood
MH  - Membrane Proteins/physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Models, Biological
MH  - Molecular Chaperones/physiology
MH  - NF-KappaB Inhibitor alpha
MH  - Oxidative Stress
MH  - Phosphorylation
MH  - Protein Folding
MH  - Protein Processing, Post-Translational
MH  - Serpins
MH  - Stress, Physiological/*complications/physiopathology
MH  - eIF-2 Kinase/physiology
EDAT- 2004/06/24 05:00
MHDA- 2005/01/11 09:00
CRDT- 2004/06/24 05:00
PHST- 2004/06/24 05:00 [pubmed]
PHST- 2005/01/11 09:00 [medline]
PHST- 2004/06/24 05:00 [entrez]
AID - 01.CIR.0000134487.51510.97 [pii]
AID - 10.1161/01.CIR.0000134487.51510.97 [doi]
PST - ppublish
SO  - Circulation. 2004 Jul 13;110(2):207-13. doi: 10.1161/01.CIR.0000134487.51510.97. 
      Epub 2004 Jun 21.