Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA.
Diabetic patients are particularly susceptible to cardiomyopathy independent of vascular disease, and recent evidence implicates cell death as a contributing factor. Given its protective role against apoptosis, we hypothesized that dietary n-6 polyunsaturated fatty acid (PUFA) may well decrease the incidence of this mode of cardiac cell death after diabetes. Male Wistar rats were first fed a diet rich in n-6 PUFA [20% (wt/wt) sunflower oil] for 4 wk followed by streptozotocin (STZ, 55 mg/kg) to induce diabetes. After a brief period of hyperglycemia (4 days), hearts were excised for functional, morphological, and biochemical analysis. In diabetic rats, n-6 PUFA decreased caspase-3 activity, crucial for myocardial apoptosis. However, cardiac necrosis, an alternative mode of cell death, increased. In these hearts, a rise in linoleic acid and depleted cardiac glutathione could explain this "switch" to necrotic cell death. Additionally, mitochondrial abnormalities, impaired substrate utilization, and enhanced triglyceride accumulation could have also contributed to a decline in cardiac function in these animals. Our study provides evidence that, in contrast to other models of diabetic cardiomyopathy that exhibit cardiac dysfunction only after chronic hyperglycemia, n-6 PUFA feeding coupled with only 4 days of diabetes precipitated metabolic and contractile abnormalities in the heart. Thus, although promoted as being beneficial, excess n-6 PUFA, with its predisposition to induce obesity, insulin resistance, and ultimately diabetes, could accelerate myocardial abnormalities in diabetic patients.
Div. of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Univ. of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3.
Sanjoy
S
Ghosh
Dake
D
Qi
Ding
D
An
Thomas
T
Pulinilkunnil
Ashraf
A
Abrahani
Kuo-Hsing
KH
Kuo
Richard B
RB
Wambolt
Michael
M
Allard
Sheila M
SM
Innis
Brian
B
Rodrigues
D000821:Animal Feed; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D004041:Dietary Fats / Q000494:pharmacology; D043371:Fatty Acids, Omega-6 / Q000493:pharmacokinetics*; D005947:Glucose / Q000378:metabolism; D006334:Heart Function Tests; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009336:Necrosis; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D010938:Plant Oils / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D000074242:Sunflower Oil
D004041:Dietary Fats; D043371:Fatty Acids, Omega-6; D010168:Palmitates; D010938:Plant Oils; D000074242:Sunflower Oil; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005947:Glucose