Abstract 3293: Persistent Angiotensin II Independent Activation of Mineralocorticoid Receptor Signaling is Associated With the Deterioration of Cardiac Function Induced by Chronic Diabetes Mellitus
Background: We reported previously LV dysfunction induced by short-term diabetes (DM) was ameliorated in angiotensin II type1a receptor knockout mice (KO). However, long-term DM may induce LV dysfunction through angiotensin II (AII) independent activation of renin-angiotensin-aldosterone system.
Goal: The goal of this study was to determine if long-term DM induces LV dysfunction through AII independent mineralocorticoid receptor (MR) activation.
Method: Male wild-type mice (WT) or KO was randomized to DM group with a single injection of streptozotocin (STZ, 200 mg/kg BW ip) or vehicle group (V). They were bred during 6 or 12 weeks and some KO were fed diet supplemented with MR antagonist, eplerenone (E, 100mg/kgBW) during 12 weeks. Hemodynamic study, echocardiography and molecular analyses were done 6 or 12 weeks after injection.
Results: Blood glucose level was elevated similarly in all STZ treated groups. At 6th week LV function was impaired in WTDM and preserved in KODM. At 12th week, fractional shortening, +dP/dt and −dP/dt were depressed by 11%, 28% and 35% respectively in WTDM compared with WT-V. The systolic LV function of KODM was preserved. However, the diastolic function of KODM was also depressed by 25% in E/A and by 25% in −dP/dt compared with KO-V at 12th week. E offset the depression of those indices. The MR mRNA level at 12th week was 2.4-fold upregulated in WTDM (p<0.01) and 3.0-fold even in KODM (p<0.05), although it didn’t show any alterations in KODM at 6th week. The SERCA2a mRNA level at 12th week was depressed in WTDM by 27% (p<0.05) and even in KODM by 25% (p<0.05), although it didn’t show any alterations in KODM at 6th week. E arrested mRNA changes of MR and SERCA2a in KODM. The mRNA level of CYP11B2 (aldosterone synthase) was similar among groups in adrenal gland. However, the mRNA level of CYP11B1, a key enzyme to produce corticosterone, was upregulated in WTDM and KODM compared with respective V groups, whereas it was attenuated by E.
Conclusion: Diabetes-induced diastolic dysfunction was observed even in KO at 12 weeks after STZ injection, which was ameliorated by E. The AII independent production of corticosterone, not aldosterone, in adrenal gland and MR activation in cardiac tissue might be responsible for cardiac dysfunction induced by long-term DM.