Abstract 764: Atrial Natriuretic Peptide (ANP) Prevents Diabetic Cardiomyopathy via Suppression of NADPH Oxidase
Diabetic cardiomyopathy (DCM) is characterised by abnormalities in left ventricular (LV) function, cardiac hypertrophy and fibrosis. We have shown that ANP suppresses NADPH oxidase in vitro. We now test the hypothesis that ANP limits the functional and structural components of DCM and elucidate whether antioxidant actions contribute to this protection. After 8wks streptozotocin diabetes induces marked diastolic dysfunction in adult male rats: early/late diastolic filling (E/A ratio) is 1.3±0.0 vs 1.9±0.1 and LVdP/dtmin 3750±310 vs 6460±320mmHg/s, compared to shams (both n=15, P<0.001). Diabetes also elicits moderate systolic dysfunction, on LVdP/dtmax (5650±330 vs 7390±350mmHg/s), aortic flow velocity (0.87±0.05 vs 1.11±0.04m/s), and LV systolic pressure (82±3 vs 104±4mmHg, all n=15, P<0.005), versus shams. Marked signs of cardiac hypertrophy (LV cardiomyocyte size on H&E staining, β-myosin heavy chain expression on real-time PCR) and fibrosis (LV collagen content on sirius red staining) are also evident, as are increased NADPH oxidase activity (3.0±0.8-fold) and gp91phox gene expression (3.4±1.2-fold, both n=16, P<0.05 versus sham). The DCM phenotype is completely prevented by insulin. ANP treatment (10pmol/kg/min sc, n=13) over the last 4wks of diabetes potently attenuates LV expression of β-myosin heavy chain (by 69±5%, P<0.001) and gp91phox (by 79±7%, P<0.05). NADPH oxidase activity is also decreased, by 69±5% (P<0.01). ANP also improves E/A ratio, by 22±6% (P<0.05). LVdP/dtmin also tended to improve with ANP, by 15±9%. Moreover, ANP increases aortic flow velocity and velocity of circumferential fibre shortening, by 19±7% (P<0.05) and 14±6% (P=0.07). Conversely, ramipril (1mg/kg/day, n=12) and tempol (1.5mmol/kg/day sc, n=11) only improve diastolic (not systolic) function. The antioxidant (but not the ACE inhibitor) also attenuates cardiac fibrosis. In conclusion, our results demonstrate that ANP ameliorates diabetes-induced disturbances in both LV function and NADPH oxidase, and is superior to ramipril in this regard. These studies may facilitate development of innovative pharmacotherapies specifically for diabetic cardiomyopathy, based on natriuretic peptide and/or antioxidant approaches.