Abstract 16145: Constitutively Active GSK-3α Causes Cardiac Dysfunction in Aging Mice
Expression and phosphorylation of glycogen synthase kinase-3 alpha (GSK-3α) is increased in aging hearts. We have previously reported that overexpression of GSK-3α in the heart resulted in an accelerated aging phenotype, including cardiac dysfunction, increased fibrosis and apoptosis. However, the role of phosphorylation of GSK-3α in the aging process is unknown. We studied whether phosphorylation of GSK-3α protects against cardiac aging in the unphosphrylatable and thus constitutively active GSK-3αS21A knock-in mice (αKI). At 13 months, left ventricular weight (LVW)/body weight(BW) ratio (mg/g) and LVW/tibia length (TL) ratio (mg/mm) were significantly lower in αKI than in littermate wild type mice (WT) (LVW/BW: 2.92±0.07 vs. 3.42±0.22, p<0.05; LVW/TL: 4.54±0.12 vs. 6.1±0.39, p<0.01). The cross-sectional area of cardiac myocytes was also significantly smaller in αKI than in WT (0.83±0.03 vs. 1.00±0.04, p<0.05). These data suggest that constitutively active GSK-3α inhibited cardiac growth in aging heart. Echocardiographic measurements showed that the diastolic posterior wall thickness in αKI was significantly smaller than that in WT (0.78±0.03 vs. 0.88±0.04, p<0.05). The ejection fraction (EF) and fractional shortening (FS) were significantly lower in αKI than in WT (EF: 0.57±0.02 vs. 0.63±0.01, p<0.05; FS (%): 24.4±1.1 vs. 28.5±0.8, p<0.05). Similarly, +dP/dt (mmHg/sec) was significantly lower in αKI than in NTg (5850±184 vs. 7100±485, p<0.05), and - dP/dt (mmHg/sec) was also significantly lower in αKI than in WT (5200±311 vs. 6100±560, p<0.05). These data indicate that constitutively active GSK-3α promotes cardiac dysfunction during aging. Histological analysis revealed that aging αKI hearts had significantly more fibrosis (%fibrosis, 2.83±0.07 vs. 2.27±0.16, p<0.05) and significantly more apoptosis (%TUNEL-positive nuclei, 0.104±0.010 vs. 0.065±0.007, p<0.05) than age-matched WT hearts. These data demonstrate that active GSK-3α enhances aging-related cardiac pathology. In conclusion, constitutively active GSK-3α causes cardiac dysfunction and increases cardiac fibrosis and apoptosis during aging. Phosphorylation of GSK-3α at serine 21 is protective during aging.
- © 2012 by American Heart Association, Inc.