Abstract 12003: Conditional Deletion or Inducible Overexpression of GLUT1 in Cardiomyocytes Influences Fibrosis and Mitochondrial Function but Not Contractile Function Following Transverse Aortic Constriction
Induction of endogenous GLUT1 in response to pressure overload hypertrophy (POH) has been suggested to be cardioprotective. To determine if endogenous GLUT1 expression is required for the initial functional adaptation to POH, we generated cardiomyocyte-restricted GLUT1 knockout mice (G1KO), and compared their response to POH with that of controls and to mice with doxycycline (Tet-on) inducible short-term cardiomyocyte-restricted overexpression of GLUT1 (G1HA). Transverse aortic constriction (TAC) was performed in 6-week-old mice (n=5 per group), and transgene induction in G1HA mice was initiated 2 days prior to TAC. Four weeks after TAC, in vivo systolic and diastolic pressures were assessed by left ventricle catheterization, and mitochondrial respirations in response to palmitoyl-canitine (PC) were measured in saponin-permeabilized cardiac fibers. Control and G1KO TAC mice developed equivalent cardiac hypertrophy relative to shams, whereas G1HA mice developed more cardiac hypertrophy following TAC than their controls. Cardiac fibrosis was increased to the same extent in control and G1KO after TAC, but was 50% reduced in G1HA vs. control TAC. Left ventricle end diastolic pressure was increased and +dP/dt was reduced to the same extent in G1KO and G1HA relative to their controls following TAC. State 3 mitochondrial respirations were reduced in both control (38% vs. sham, p<0.05) and G1KO mice (28.6% vs. sham, p<0.05) after TAC, but were preserved in G1HA mice. ATP production was also equivalently reduced in control and G1KO mice following TAC, but was maintained in G1HA mice. Thus, cardiomyocyte-restricted GLUT1 deletion does not exacerbate POH-induced cardiac mitochondrial or contractile dysfunction. By contrast, short-term GLUT1 overexpression at the onset of pressure overload, while preserving mitochondrial function and reducing fibrosis, is not sufficient to prevent LV dysfunction.
- © 2011 by American Heart Association, Inc.