Oral Administration of the Glutathione Peroxidase Mimic SYI-2074 Ameliorates Post-MI Heart Failure in Type 1 Diabetes Mellitus

Heart Failure (HF) has been documented to be the most prevalent complication in type 1 diabetes mellitus (DM) patients surviving a myocardial infarction (MI). We have previously shown that oxidative stress is markedly accentuated in the surviving tissues of type 1 diabetic post-MI rat hearts during HF. In the present study, we tested whether oral administration of the glutathione peroxidase mimic, SYI-2074, confers cardioprotection against HF in the setting of MI associated with type 1 DM. Type 1 DM was induced in male Sprague-Dawley rats by a single injection of streptozotocin (65 mg/kg I.P.). Two weeks after induction of type 1 DM, rats underwent coronary artery ligation to induce MI. Diabetic MI rats were randomly assigned to receive either SYI-2074 (5 mg/kg) or vehicle (water) by gastric lavage beginning 6 hours post-MI and continuing for 28 days. Residual in vivo cardiac function in both groups of diabetes MI rats was assessed by echocardiography. Myocardial concentrations of products of free radical-mediated lipid peroxidation, F2-Isoprostanes (F2-IsoPs) and Isofurans (IsoFs), were measured by gas chromatography mass spectrometric (GC/MS) assay. Treatment of diabetic MI rats with SYI-2074 improved myocardial contractility measured 28 days post-MI ([Fractional Shortening: SYI-2074, 34.0 ± 0.8 % (n=4) vs. vehicle, 28.4 ± 1.5 % (n=4), p<0.05; Ejection Fraction: SYI-2074, 68.4 ± 1.1 % (n=4) vs. vehicle, 60.7 ± 2.3 % (n=4), p<0.05]). Interestingly, post-infarcted DM rats treated with SYI-2074 showed enlarged left ventricular (LV) dimension compared to the diabetic MI rats that received vehicle ([LV internal dimension, diastolic: SYI-2074, 0.78 ± 0.02 cm (n=4) vs. vehicle, 0.70 ± 0.02 cm (n=4), p<0.05]). Myocardial levels of F2-IsoPs and IsoFs (ng/g tissue) showed a modest, but statistically insignificant, trend toward increase in diabetic post-MI rats treated with SYI-2074 ([F2-IsoPs: SYI-2074, 2.5 ± 0.1 (n=3) vs. vehicle, 1.7 ± 0.3 (n=4), p=0.100; IsoFs: SYI-2074, 1.9 ± 0.6 (n=3) vs. vehicle, 1.0 ± 0.1 (n=4), p=0.06]). Collectively, these data suggest that the diabetic heart may have a decreased capacity to remodel after MI and that treatment with SYI-2074 may attenuate subsequent HF by inducing adaptive cardiac remodeling. The absence of a lowering effect on oxidative stress in diabetic post-MI heart coincident with administration of the glutathione peroxidase mimic SYI-2074 was an unexpected outcome of this pre-clinical study that warrants further investigation.