Abstract 3889: Pyruvate Dehydrogenase Kinase 4 (PDK4) Deficiency Does Not Impair the Cardiac Metabolic or Contractile Response to Pressure Overload Hypertrophy
Pyruvate dehydrogenase kinase 4 (PDK4) decreases glucose oxidation by an inhibitory phosphorylation of the pyruvate dehydrogenase complex. PDK4 expression is induced in response to metabolic stimuli, such as a high fat diet, and PDK4 expression is reduced in the failing human heart. To determine the role of PDK4 in the maintenance of cardiac contractile and metabolic function in response to pressure overload, we examined PDK4−/− mice following 4wk of transverse aortic banding (TAB). Heart weight to body weight ratios (HW/BW (mg/g)) were significantly increased by TAB in either group vs. sham-operated mice (5.7±0.3 TAB-PDK4−/− and 6.1±0.3 TAB-WT vs. 4.4±0.2 Sham-PDK4−/− and 4.5±0.1 Sham-WT; n=6 –10, P<0.001). Cardiac function as assessed by echocardiography revealed a trend toward an increase in stroke volume (μL) in TAB-PDK4−/− vs. TAB-WT mice (43.9±2.4 TAB-PDK4−/− and 37.5±2.1 TAB-WT; n=6 – 8, P=0.069). Left-ventricular (LV) catheterization revealed equivalent increases in both TAB groups compared to sham-operated animals for LV systolic pressure and LV developed pressure (n=5–7, P<0.01). The peak rate of LV pressure increase (+dP/dt; mmHg/sec) was reduced in TAB-WT mice vs. all groups (P<0.03), while TAB-PDK4−/− mice had the highest +dP/dt (8054±636). The peak rate of LV pressure decrease (−dP/dt) was significantly increased in TAB-PDK4−/− relative to TAB-WT (−9616±1239 TAB-PDK4−/− and −6545±552 TAB-WT, P<0.02). Relative to shams, fibrosis was increased in both TAB groups as measured by trichrome staining, but fibrosis was significantly lower in the TAB-PDK4−/− mice vs. TAB-WT mice (11.9%±0.4% TAB-PDK4−/− and 16.4%±1.3% TAB-WT; n=3, P<0.005). Surprisingly, there was no significant difference in glucose oxidation or glycolysis in TAB-PDK4−/− vs. TAB-WT as assessed in isolated working hearts. This might partially be accounted for by a 50% reduction in cardiac PDK4 content in TAB-WT. Thus, PDK4 deficiency appears to be protective in the cardiac response to pressure overload hypertrophy, thereby suggesting that reduced PDK4 expression in response to pressure overload might be an adaptive response.
This research has received full or partial funding support from the American Heart Association, Western States Affiliate (California, Nevada & Utah).