Abstract 13184: MEK1 Rescues Cardiac Dysfunction Caused by Overexpressed GSK-3α During Aging and Hemodynamic Pressure Overload
Expression of glycogen synthase kinase-3 alpha (GSK-3α) is increased in aging hearts and those subjected to hemodynamic overload. Overexpressed GSK-3α inhibits ERK and enhances pressure overload (PO)-induced cardiac dysfunction. We studied whether suppression of the MEK/ERK pathway contributes to cardiac responses caused by overexpressed GSK-3α, using transgenic mouse (Tg) models. MEK1/GSK-3α bigenic mice (Bigenic) were obtained by crossing cardiac-specific GSK-3α Tg (Tg-GSK) and constitutively active MEK1 Tg (Tg-MEK). Suppression of ERK phosphorylation in Tg-GSK was restored in Bigenic. At 12 months, LV weight/tibia length (mg/mm) was significantly smaller in Tg-GSK than in non-transgenic mice (NTg) (4.3±0.4 vs 5.1±0.3, p<0.05), but it was not significantly different between Tg-MEK and Bigenic (7.5±0.7, 7.2±0.6). The cell size was significantly smaller in Tg-GSK than in NTg (0.84±0.01, 1.00±0.01, p<0.01), but was not significantly different between Bigenic and Tg-MEK (1.46±0.09, 1.46±0.02). These data suggest that MEK1 reverses the inhibition of cardiac growth by overexpressed GSK-3α. The ejection fraction (EF) and fractional shortening (FS) were significantly lower in Tg-GSK than in NTg (EF: 0.56±0.05, 0.68±0.01, p<0.05; FS (%): 25±3, 32±1, p<0.05). The EF and FS were not significantly different between Bigenic and Tg-MEK (EF: 0.81±0.02, 0.78±0.05; FS (%): 43±2, 40±5), but were significantly higher in Bigenic than in Tg-GSK. Similarly, +dP/dt (mmHg/sec) was significantly lower in Tg-GSK than in NTg (4950±210, 7100±485, p<0.05), but was maintained in Bigenic (7500±866). After PO, the EF and FS were significantly reduced in Tg-GSK compared to sham (0.53±0.05 vs 0.68±0.02, p<0.05 and 23±3 vs 31±2, p<0.05), but not in NTg (0.66±0.02 vs 0.70±0.02 and 31±2 vs 33±2), Tg-MEK (0.76±0.04 vs 0.79±0.04 and 41±4 vs 39±3) or Bigenic (0.72±0.01 vs 0.77±0.03 and 35±1 vs 40±3). There was no significant difference in EF and FS between Bigenic and Tg-MEK. These data indicate that the reversal of ERK inhibition attenuates suppression of hypertrophy and cardiac dysfunction caused by overexpressed GSK-3α. In conclusion, inhibition of the MEK1-ERK pathway mediates hypertrophy suppression and cardiac dysfunction caused by overexpressed GSK-3α in the heart.
- © 2010 by American Heart Association, Inc.