Abstract 852: Genetic Ablation of Angiotensin II Type1a Receptor Ameliorates Cardiac Diastolic Dysfunction Induced by Diabetes Mellitus through the Improvement of Calcium Handling
Although presence of diabetes mellitus (DM) is associated with decompensated heart failure and poor clinical outcome, independent of coronary artery disease and hypertension, mechanisms responsible for diabetes-related cardiac dysfunction have not been elucidated. We hypothesized that renin-angiotensin system (RAS) is involved in the DM-induced cardiac dysfunction. The goal of this study is to determine whether genetically blocked RAS ameliorates cardiac dysfunction induced by DM.
Methods: DM was induced in 100 male wild-type mice (WT) or angiotensin II type 1a receptor knockout mice (KO) by a single injection of streptozotocin (STZ, 200 mg/kg BW ip). Hemodynamic measurement using catheter-tip manometer, echocardiography, morphological and molecular analyses were performed 6 weeks after STZ or vehicle injection.
Results: Blood glucose level was higher both in STZ-treated WT (WT-DM, 477±94mg/dl) and KO (KO-DM, 482±95mg/dl) compared with vehicle-treated WT (WT-C, 176±34mg/dl) or vehicle-treated KO (KO-C, 168±38 mg/dl). BW loss after 6 weeks was significant in WT-DM (-4.7±2.2g), but not in others (WT-C +2.7±1.3g, KO-DM -1.2±3.1g, KO-C +4.5±3.5g). E wave on transmitral doppler flow was lower in WT-DM than WT-C (p<0.004). E/A ratio tended to be lower in WT-DM than WT-C (1.44±0.6 vs. 1.97±0.48, p<0.06). Peak -dP/dt was lower in WT-DM than WT-C (3575±1005 vs. 4915±531 mmHg/sec, p<0.01). There was no difference in these parameters between KO-DM and KO-C (E/A, 2.2±0.6 vs. 2.0±0.4;-dP/dt, 6124±3557 vs. 5596±1414 mmHg/sec). Left ventricular end-diastolic pressure was similar in the 4 groups. The mRNA level of angiotensinogen in the LV myocardium was 1.9 fold upregulated in WT-DM (p=0.001) and 1.7 fold in KO-DM (p=0.04) compared with each control group, showing activation of RAS by DM. Sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) mRNA and protein levels were depressed by 44% (p=0.008) and by 61% (p=0.034) in WT-DM, as compared with WT-C. However, there was no significant change between KO-DM and KO-C. Phospholamban mRNA and protein levels were similar in the 4 groups.
Conclusions: The RAS blockade is beneficial in preventing DM-induced diastolic dysfunction. Alterations in Ca handling may play a role in mediating DM-induced cardiac dysfunction.