PMID- 20828387
OWN - NLM
STAT- MEDLINE
DCOM- 20101123
LR  - 20231213
IS  - 1475-2840 (Electronic)
IS  - 1475-2840 (Linking)
VI  - 9
DP  - 2010 Sep 9
TI  - Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol.
PG  - 49
LID - 10.1186/1475-2840-9-49 [doi]
AB  - BACKGROUND: Hyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic 
      cardiomyopathy by inducing oxidative stress and attenuating peroxisome 
      proliferator- activated receptor (PPAR) gamma. However, their synergistic 
      contribution is not clear. METHODS: Diabetic Akita (Ins2+/-) and 
      hyperhomocysteinemic cystathionine beta synthase mutant (CBS+/-) were used for 
      M-mode echocardiography at the age of four and twenty four weeks. The cardiac 
      rings from WT, Akita and hybrid (Ins2+/-/CBS+/-) of Akita and CBS+/- were treated 
      with different doses of acetylcholine (an endothelial dependent vasodilator). 
      High performance liquid chromatography (HPLC) was performed for determining 
      plasma homocysteine (Hcy) level in the above groups. Akita was treated with 
      ciglitazone (CZ) - a PPAR gamma agonist and tempol-an anti-oxidant, separately 
      and their effects on cardiac remodeling were assessed. RESULTS: At twenty four 
      week, Akita mice were hyperglycemic and HHcy. They have increased end diastolic 
      diameter (EDD). In their heart PPAR gamma, tissue inhibitor of 
      metalloproteinase-4 (TIMP-4) and anti-oxidant thioredoxin were attenuated whereas 
      matrix metalloproteinase (MMP)-9, TIMP-3 and NADPH oxidase 4 (NOX4) were induced. 
      Interestingly, they showed synergism between HHcy and hyperglycemia for 
      endothelial-myocyte (E-M) uncoupling. Additionally, treatment with CZ alleviated 
      MMP-9 activity and fibrosis, and improved EDD. On the other hand, treatment with 
      tempol reversed cardiac remodeling in part by restoring the expressions of 
      TIMP-3,-4, thioredoxin and MMP-9. CONCLUSIONS: Endogenous homocysteine 
      exacerbates diabetic cardiomyopathy by attenuating PPAR gamma and inducing E-M 
      uncoupling leading to diastolic dysfunction. PPAR gamma agonist and tempol 
      mitigates oxidative stress and ameliorates diastolic dysfunction in diabetes.
FAU - Mishra, Paras K
AU  - Mishra PK
AD  - Department of Physiology & Biophysics, School of Medicine, University of 
      Louisville, Louisville, Kentucky 40202, USA.
FAU - Tyagi, Neetu
AU  - Tyagi N
FAU - Sen, Utpal
AU  - Sen U
FAU - Joshua, Irving G
AU  - Joshua IG
FAU - Tyagi, Suresh C
AU  - Tyagi SC
LA  - eng
GR  - HL-71010/HL/NHLBI NIH HHS/United States
GR  - HL-74185/HL/NHLBI NIH HHS/United States
GR  - HL-88012/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100909
PL  - England
TA  - Cardiovasc Diabetol
JT  - Cardiovascular diabetology
JID - 101147637
RN  - 0 (Antioxidants)
RN  - 0 (Cyclic N-Oxides)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (PPAR gamma)
RN  - 0 (Spin Labels)
RN  - 0 (Thiazolidinediones)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-3)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.- (Nox4 protein, mouse)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - U78ZX2F65X (tempol)
RN  - U8QXS1WU8G (ciglitazone)
SB  - IM
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - *Cardiomyopathies/drug therapy/etiology/metabolism
MH  - Cyclic N-Oxides/*pharmacology
MH  - Diabetes Complications/drug therapy/metabolism
MH  - *Diabetes Mellitus, Type 1/complications/drug therapy/metabolism
MH  - Drug Synergism
MH  - Hyperglycemia/drug therapy/metabolism
MH  - *Hyperhomocysteinemia/complications/drug therapy/metabolism
MH  - Hypoglycemic Agents/pharmacology
MH  - Male
MH  - Matrix Metalloproteinase 2/genetics/metabolism
MH  - Matrix Metalloproteinase 9/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NADPH Oxidase 4
MH  - NADPH Oxidases/genetics/metabolism
MH  - Oxidative Stress/drug effects/physiology
MH  - PPAR gamma/*agonists/genetics/metabolism
MH  - Spin Labels
MH  - Thiazolidinediones/*pharmacology
MH  - Tissue Inhibitor of Metalloproteinase-3/metabolism
MH  - Tissue Inhibitor of Metalloproteinases/metabolism
MH  - Tissue Inhibitor of Metalloproteinase-4
PMC - PMC2944245
EDAT- 2010/09/11 06:00
MHDA- 2010/12/14 06:00
PMCR- 2010/09/09
CRDT- 2010/09/11 06:00
PHST- 2010/08/09 00:00 [received]
PHST- 2010/09/09 00:00 [accepted]
PHST- 2010/09/11 06:00 [entrez]
PHST- 2010/09/11 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2010/09/09 00:00 [pmc-release]
AID - 1475-2840-9-49 [pii]
AID - 10.1186/1475-2840-9-49 [doi]
PST - epublish
SO  - Cardiovasc Diabetol. 2010 Sep 9;9:49. doi: 10.1186/1475-2840-9-49.