Abstract 18631: PKA Inhibition Ameliorates Cardiac Dysfunction In High-fat Feeding Induced Type II Diabetic Mice

Abstract

Background: In type 2 diabetic (T2D) patients, the sympathoadrenergic system (SAS) is chronically activated, resulting in chronic protein kinase A (PKA) activation. T2D causes cardiac dysfunction. Objective: To test the hypothesis that PKA plays an important role in diabetic cardiac dysfunction. Methods: PKA inhibition (PKI) transgenic (TG, n=18) and nontransgenic littermate control (NLC, n=20) mice (3-month old) were fed with high fat food (D12451, Research Diet) for 6 months. The body weight (BW) was measured twice a week. Intra-LV hemodynamic, heart weight, liver weight, lung weight, and tibia length were determined at the end point. Myocyte contraction was analyzed. The lean body weight was measured after removing water and fat content of the entire carcass. Inflammatory cell infiltration and fibrosis were determined with MAO staining and Masson’s trichrome staining respectively. Results: 1. The BW of both groups was increased similarly (NLC: from 23.8±3.6g to 45.8±5.6g; TG: from 24.2±3.9g to 46.4±5.6g). Lean body weight and fat composition were not different. 2. The PKI TG group had better cardiac function when examined with intra-LV hemodynamic measurements: (1). The maximal systolic pressure (mmHg) of TG (107.8±4.49) was significantly higher than that of NLC (83.0±8.1) mice. (2). The end diastolic pressure (EDP, mmHg) of TG (2.7 ± 2.2) was significantly lower compared to WT mice (11.5 ± 3.3); (3). Maximum dp/dt (mmHg/s) was significantly higher in PKI TG (7628.0 ± 537.5) than in NLC mice (5021.4 ± 806.2); (4). The relaxation rate of the heart (minimum -dp/dt in mmHg/s) was significantly better in TG (-7159.5 ± 543.0) than in NLC mice (-5334.7 ± 516.2); (5). The HW/BW (mg/g) was significantly less in TG mice (4.6 ± 0.2) than in control mice (5.2 ± 0.2). (6). The lung weight/BW and liver Weight/BW were also reduced in TG mice. (7). At the myocyte level, myocyte contraction amplitude was slightly but significantly greater in TG myocytes than in NLC myocytes. Myocyte relaxation rate was significantly faster in TG myocytes. (8). TG hearts had less inflammatory cell infiltration and fibrosis than control hearts. Conclusion: PKA inhibition ameliorates cardiac remodeling and preserves cardiac function in high fat feeding-induced diabetic mice.