PMID- 12734208
OWN - NLM
STAT- MEDLINE
DCOM- 20030814
LR  - 20220711
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 28
DP  - 2003 Jul 11
TI  - Increased production of 12/15 lipoxygenase eicosanoids accelerates 
      monocyte/endothelial interactions in diabetic db/db mice.
PG  - 25369-75
AB  - Atherosclerosis is a major complication of diabetes. Up to 16 weeks of age, the 
      db/db mouse is insulin-resistant and hyperglycemic and is a good model of Type 2 
      diabetes. After approximately 16 weeks of age, the mice develop pancreatic beta 
      cell failure that can progress to a Type 1 diabetes phenotype. We have previously 
      shown that glucose increases production of endothelial 12/15 lipoxygenase 
      (12/15LO) products in vitro. In young 10-week-old Type 2 diabetic db/db mice, we 
      found significant elevations in levels of urinary 12/15LO products, 
      12S-hydroxyeicosatetraenoic acid (12S-HETE) and 13S-hydroxyoctadecaenoic acid 
      (13S-HODE) in vivo compared with C57BLKS/J mice. Using isolated primary aortic 
      endothelial cells (ECs) from db/db mice and WEHI78/24 mouse monocyte cells in 
      static adhesion assays, we found increased WEHI monocyte adhesion to db/db ECs 
      (14 +/- 2 monocytes/field for db/db ECs versus 4 +/- 1 monocytes/field for 
      C57BLKS/J ECs, p < 0.002). Thus, ECs from db/db mice appear to be "pre-activated" 
      to bind monocytes. Analysis of db/db ECs revealed a 2-fold elevation in 12/15LO 
      protein compared with C57BLKS/J EC. To determine that 12/15LO products were 
      responsible for the increased monocyte adhesion observed with db/db ECs, we 
      inhibited expression of murine 12/15LO using either an adenovirus expressing a 
      ribozyme to 12/15LO (AdRZ) or with the 12/15LO inhibitor 
      cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate. Treatment of db/db ECs for 48 h with 
      AdRZ or 4 h with 10 microm cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate 
      significantly reduced monocyte adhesion to db/db endothelium (p < 0.009). Thus, 
      inhibition of the murine 12/15LO in db/db mice significantly reduced 
      monocyte/endothelial interactions. We also found that adhesion of monocytes to 
      diabetic db/db ECs was mediated by interactions of alpha4beta1 integrin on 
      monocytes with endothelial vascular cell adhesion molecule 1 and connecting 
      segment 1 fibronectin and interactions of beta2 integrins with endothelial 
      intercellular adhesion molecule 1. In summary, regulation of the 12/15LO pathway 
      is important for mediating early vascular changes in diabetes. Modulation of the 
      12/15LO pathway in the vessel wall may provide therapeutic benefit for early 
      vascular inflammatory events in diabetes.
FAU - Hatley, Melissa E
AU  - Hatley ME
AD  - Division of Endocrinology and Metabolism and Cardiovascular Research Center, 
      University of Virginia, Charlottesville, Virginia 22908, USA.
FAU - Srinivasan, Suseela
AU  - Srinivasan S
FAU - Reilly, Kelly B
AU  - Reilly KB
FAU - Bolick, David T
AU  - Bolick DT
FAU - Hedrick, Catherine C
AU  - Hedrick CC
LA  - eng
GR  - DK39721/DK/NIDDK NIH HHS/United States
GR  - P01 HL55798-06/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030506
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Eicosanoids)
RN  - 0 (Fibronectins)
RN  - 0 (Linoleic Acids)
RN  - 0 (Reactive Oxygen Species)
RN  - 5204-88-6 (13-hydroxy-9,11-octadecadienoic acid)
RN  - 59985-28-3 (12-Hydroxy-5,8,10,14-eicosatetraenoic Acid)
RN  - EC 1.13.11.31 (Arachidonate 12-Lipoxygenase)
RN  - EC 1.13.11.33 (Arachidonate 15-Lipoxygenase)
SB  - IM
EIN - J Biol Chem. 2003 Dec 12;278(50):50818
MH  - 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/urine
MH  - Animals
MH  - Aorta/metabolism
MH  - Arachidonate 12-Lipoxygenase/*biosynthesis
MH  - Arachidonate 15-Lipoxygenase/*biosynthesis
MH  - Cell Adhesion
MH  - Eicosanoids/metabolism
MH  - Endothelium, Vascular/*metabolism
MH  - Fibronectins/metabolism
MH  - Flow Cytometry
MH  - Immunoassay
MH  - Inflammation
MH  - Islets of Langerhans/metabolism
MH  - Linoleic Acids/urine
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/metabolism
MH  - Monocytes/*metabolism
MH  - Phenotype
MH  - Reactive Oxygen Species
EDAT- 2003/05/08 05:00
MHDA- 2003/08/15 05:00
CRDT- 2003/05/08 05:00
PHST- 2003/05/08 05:00 [pubmed]
PHST- 2003/08/15 05:00 [medline]
PHST- 2003/05/08 05:00 [entrez]
AID - S0021-9258(19)75048-0 [pii]
AID - 10.1074/jbc.M301175200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Jul 11;278(28):25369-75. doi: 10.1074/jbc.M301175200. Epub 2003 
      May 6.