PPAR gamma agonist normalizes glomerular filtration rate, tissue levels of homocysteine, and attenuates endothelial-myocyte uncoupling in alloxan induced diabetic mice.
BACKGROUND
Homocysteine (Hcy) is an independent cardiovascular risk factor; however, in diabetes, the role of tissue Hcy leading to cardiac dysfunction is unclear.


OBJECTIVE
To determine whether tissue Hcy caused endothelial-myocyte uncoupling and ventricular dysfunction in diabetes.


METHODS
Diabetes was created in C57BL/6J male mice by injecting 65 mg/kg alloxan. To reverse diabetic complications, ciglitazone (CZ) was administered in the drinking water. Plasma glucose, Hcy, left ventricular (LV) tissue levels of Hcy and nitric oxide (NO) were measured. Glomerular filtration rate (GFR) was measured by inulin-FITC. Endothelial-myocyte coupling was measured in cardiac rings. In vivo diastolic relaxation and LV diameters were measured by a Millar catheter in LV and by M-mode echocardiography, respectively.


RESULTS
Plasma glucose, GFR and LV tissue Hcy were increased in diabetic mice and were normalized after CZ treatment; whereas, elevated plasma Hcy level remained unchanged with or without CZ treatment. NO levels in the LV were found inversely related to tissue Hcy levels. Attenuated endothelial-myocyte function in diabetic mice was ameliorated by CZ treatment. Cardiac relaxation, the ratio of LV wall thickness to LV diameter was decreased in diabetes, and normalized after CZ treatment.


CONCLUSIONS
CZ normalized LV tissue levels of Hcy and ameliorated endothelial-myocyte coupling; therefore, specifically suggest the association of LV tissue Hcy levels with impair endothelial-myocyte function in diabetes.
Rodriguez
Walter E
WE
Department of Physiology, Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Sen
Utpal
U
Tyagi
Neetu
N
Kumar
Munish
M
Carneal
Gene
G
Aggrawal
Deep
D
Newsome
Justin
J
Tyagi
Suresh C
SC
D000496:Alloxan; D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006710:Homocysteine / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D006710:Homocysteine; D000496:Alloxan; C039671:ciglitazone