title: N-3 polyunsaturated Fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function.
abstract: OBJECTIVE
  The vasodegenerative phase of diabetic retinopathy is characterized by not only retinal vascular degeneration but also inadequate vascular repair due to compromised bone marrow derived endothelial progenitor cells (EPCs). We propose that n-3 polyunsaturated fatty acid (PUFA) deficiency in diabetes results in activation of the central enzyme of sphingolipid metabolism, acid sphingomyelinase (ASM) and that ASM represents a molecular metabolic link connecting the initial damage in the retina and the dysfunction of EPCs.
  
  
  METHODS
  Type 2 diabetic rats on control or docosahexaenoic acid (DHA)-rich diet were studied. The number of acellular capillaries in the retinas was assessed by trypsin digest. mRNA levels of interleukin (IL)-1β, IL-6, intracellular adhesion molecule (ICAM)-1 in the retinas from diabetic animals were compared to controls and ASM protein was assessed by western analysis. EPCs were isolated from blood and bone marrow and their numbers and ability to form colonies in vitro, ASM activity and lipid profiles were determined.
  
  
  RESULTS
  DHA-rich diet prevented diabetes-induced increase in the number of retinal acellular capillaries and significantly enhanced the life span of type 2 diabetic animals. DHA-rich diet blocked upregulation of ASM and other inflammatory markers in diabetic retina and prevented the increase in ASM activity in EPCs, normalized the numbers of circulating EPCs and improved EPC colony formation.
  
  
  CONCLUSIONS
  In a type 2 diabetes animal model, DHA-rich diet fully prevented retinal vascular pathology through inhibition of ASM in both retina and EPCs, leading to a concomitant suppression of retinal inflammation and correction of EPC number and function.
authors: Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
authors: Maria
authors: M
authors: Tikhonenko
authors: Todd A
authors: TA
authors: Lydic
authors: Madalina
authors: M
authors: Opreanu
authors: Sergio
authors: S
authors: Li Calzi
authors: Svetlana
authors: S
authors: Bozack
authors: Kelly M
authors: KM
authors: McSorley
authors: Andrew L
authors: AL
authors: Sochacki
authors: Matthew S
authors: MS
authors: Faber
authors: Sugata
authors: S
authors: Hazra
authors: Shane
authors: S
authors: Duclos
authors: Dennis
authors: D
authors: Guberski
authors: Gavin E
authors: GE
authors: Reid
authors: Maria B
authors: MB
authors: Grant
authors: Julia V
authors: JV
authors: Busik
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003930:Diabetic Retinopathy / Q000178:diet therapy* / Q000209:etiology / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051381:Rats; D012171:Retinal Vessels / Q000187:drug effects / Q000503:physiopathology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects*
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D018799:Intercellular Adhesion Molecule-1; D004281:Docosahexaenoic Acids; D013108:Sphingomyelin Phosphodiesterase
references: ILAR J. 2004;45(3):292-302
references: 15229376
references: Invest Ophthalmol Vis Sci. 2000 Nov;41(12):3972-8
references: 11053301
references: Prostaglandins Leukot Essent Fatty Acids. 2002 Oct;67(4):203-10
references: 12401433
references: Diabet Med. 1999 Sep;16(9):710-5
references: 10510946
references: Invest Ophthalmol Vis Sci. 2011 Oct 21;52(11):8278-86
references: 21931131
references: J Clin Invest. 1996 Jun 15;97(12):2883-90
references: 8675702
references: Circulation. 2007 Jun 26;115(25):3165-72
references: 17562958
references: Methods. 2005 Jun;36(2):207-24
references: 15894491
references: Mol Biol Cell. 2005 Dec;16(12):5773-83
references: 16207810
references: J Am Coll Cardiol. 2005 May 3;45(9):1449-57
references: 15862417
references: Diabetes. 2005 May;54(5):1559-65
references: 15855346
references: Mol Med. 2008 May-Jun;14(5-6):301-8
references: 18309377
references: Atherosclerosis. 2009 Nov;207(1):213-9
references: 19406403
references: J Cell Physiol. 2000 Sep;184(3):285-300
references: 10911359
references: Diabetes. 2010 Jan;59(1):219-27
references: 19875612
references: Diabetes. 2011 Sep;60(9):2370-8
references: 21771974
references: Diabetes Metab Res Rev. 2011 Feb;27(2):185-94
references: 21294240
references: Prog Retin Eye Res. 2005 Jan;24(1):87-138
references: 15555528
references: Diabetes. 2006 Jan;55(1):102-9
references: 16380482
references: J Biol Chem. 1993 Sep 25;268(27):20520-3
references: 8376408
references: Prog Lipid Res. 2007 May-Jul;46(3-4):161-70
references: 17490747
references: Nature. 2004 Jun 10;429(6992):638-42
references: 15190311
references: Science. 1993 Jan 22;259(5094):519-22
references: 8424175
references: Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2140-6
references: 16857948
references: Diabetes. 2004 Jan;53(1):195-9
references: 14693715
references: Curr Mol Med. 2010 Jul;10(5):454-66
references: 20540705
references: J Med Invest. 2007 Aug;54(3-4):243-7
references: 17878672
references: Nat Rev Mol Cell Biol. 2008 Feb;9(2):139-50
references: 18216770
references: Circulation. 2003 Apr 15;107(14):1852-7
references: 12668520
references: J Cell Physiol. 2009 May;219(2):235-42
references: 19115244
references: BMC Endocr Disord. 2010 Apr 07;10:5
references: 20374643
references: Diabetologia. 2001 Sep;44 Suppl 2:S14-21
references: 11587045
references: Eur Heart J. 2006 Sep;27(18):2247-55
references: 16912055
references: Invest Ophthalmol Vis Sci. 2010 Jun;51(6):3253-63
references: 20071681
references: J Cell Biol. 2004 Mar 1;164(5):759-68
references: 14981096
references: J Mass Spectrom. 2004 Apr;39(4):412-22
references: 15103655
references: J Exp Med. 2009 Dec 21;206(13):2897-906
references: 19934019
references: J Mass Spectrom. 2004 Dec;39(12):1531-40
references: 15578747
references: Invest Ophthalmol Vis Sci. 2004 Nov;45(11):4161-6
references: 15505070
references: Biochem J. 1998 Nov 1;335 ( Pt 3):465-80
references: 9794783
references: Nat Med. 2002 Jun;8(6):607-12
references: 12042812
references: Nat Rev Mol Cell Biol. 2008 Jun;9(6):455-63
references: 18500256
references: Annu Rev Med. 2006;57:1-18
references: 16409133
references: Appl Environ Microbiol. 2005 Sep;71(9):5511-22
references: 16151144
references: Biochemistry. 2005 Dec 20;44(50):16684-94
references: 16342958
references: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Apr;27(2):283-90
references: 12657367
references: Diabetes. 2007 Jan;56(1):224-30
references: 17192486
references: Invest Ophthalmol. 1968 Feb;7(1):105-8
references: 5636782
references: Nat Med. 2007 Jul;13(7):868-873
references: 17589522
references: Diabetes. 2007 Apr;56(4):960-7
references: 17395742
references: Biochem J. 2004 Mar 1;378(Pt 2):281-92
references: 14662007
references: Arch Immunol Ther Exp (Warsz). 2007 Jul-Aug;55(4):247-59
references: 17659378
references: Metabolism. 2006 Feb;55(2):168-74
references: 16423622
references: Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4342-7
references: 16249517