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Heart disease is a leading cause of death in diabetic patients. There is growing evidence that dyslipidemia associated with diabetes contributes to the pathogenesis of diabetic cardiomyopathy, potentially through activation of protein kinase C (PKC) and/or angiotensin II (AII). This study was designed to determine whether elevated fatty acids produce cardiomyocyte mechanical dysfunction through PKC- or AII-dependent processes. Ventricular myocytes were isolated from non-diabetic and type 1 diabetic rats and cultured overnight in either normal medium or medium plus oleic acid (OA; 0.2mM). Subsets were supplemented with a non-specific PKC inhibitor bisindolylmaleimide (1µM) or angiotensin converting enzyme (ACE) inhibitor captopril (0.1µM). Isolated cardiomyocyte mechanical function was assessed using a video-based detection system. Myocyte relaxation was prolonged in non-diabetic cells cultured in OA (106 ± 3ms, n= 186) and in cells isolated from short-term (<1 week) diabetic animals (100 ± 5ms, n=55) when compared to controls (85 ± 2ms; n=164). Relaxation was normalized (OA treated myocytes) or reversed (diabetic cells) when cultured with either inhibitor. Conclusion: Fatty acid-induced cardiomyocyte dysfunction is preventable and diabetes-induced dysfunction is reversible by inhibiting cardiomyocyte derived PKC or ACE. [ABSTRACT FROM AUTHOR]

We have evidence that high glucose (HG) and high fatty acids (HFA) induce myocardial insulin resistance (IR), which mimic the effects of type 1 diabetes, and that IR is associated with abnormal excitation-contraction coupling (ECC). Although a direct link has yet to be determined, the hexosamine biosynthesis pathway (HBP) may play a central role. We have previously shown that non-specific PKC inhibition (in vitro) prevents HG-induced impaired ECC and insulin-stimulated glucose uptake in isolated cardiomyocytes, and reverses these dysfunctions in myocytes isolated from diabetic animals. We now show that inhibiting GFAT (rate limiting enzyme for the HBP), these HG effects are prevented, and the diabetes-induced abnormal ECC is reversed. For example, glucose uptake is blunted and myocyte relaxation is prolonged in HG cells by ∼30% of controls, and both are prevented by co-culture with azaserine (AZA). HFA also impairs glucose uptake and ECC. Strategies to inhibit HBP (with AZA or DON) or augment insulin sensitivity (with metformin) prevent HFA-induced abnormal ECC. Culturing cardiomyocytes from type 1 diabetic rats with DON also reverses abnormal ECC (e.g., myocyte relaxation is 2x slower in untreated diabetic myocytes than in normal cells). We suggest that the link between abnormal ECC and IR in each of our models (i.e., HG, HFA and diabetes) involves the HBP. ADA 7-04-RA-23 and N1H R01HL66895 (AJD) [ABSTRACT FROM AUTHOR]