Constitutively active MEK1 rescues cardiac dysfunction caused by overexpressed GSK-3α during aging and hemodynamic pressure overload.
Expression of 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 MEK1/ERK pathway contributes to cardiac responses induced by overexpressed GSK-3α using constitutively active MEK1 (CA-MEK1)/GSK-3α bigenic mice (bigenic mice), which were obtained by crossing cardiac-specific GSK-3α transgenic mice (Tg-GSK) and cardiac-specific CA-MEK1 transgenic mice (Tg-MEK1). The suppression of ERK phosphorylation observed in Tg-GSK was eliminated in bigenic mice. At 12 mo, left ventricular (LV) weight/tibia length, LV weight/body weight, and cardiac myocyte size were significantly smaller in Tg-GSK than in nontransgenic mice (NTg), but were not significantly different between Tg-MEK1 and bigenic mice. The LV ejection fraction (LVEF), fractional shortening (FS), and change in pressure over time were significantly lower in Tg-GSK than in NTg, but were not significantly different between bigenic mice and Tg-MEK1. The increase in apoptosis in Tg-GSK was abolished in bigenic mice, although the increase in fibrosis was not. After PO, the decrease in cardiac hypertrophy and the enhancement of apoptosis seen in Tg-GSK were abrogated in bigenic mice. After PO, the LVEF and FS were significantly reduced in Tg-GSK compared with its sham, but not in NTg, Tg-MEK1, or bigenic mice compared with their respective shams. There was no significant difference in LVEF and FS between bigenic mice and Tg-MEK1 after PO. In conclusion, inhibition of the MEK1/ERK pathway mediates the hypertrophy suppression and cardiac dysfunction caused by GSK-3α overexpression in cardiac myocytes.
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry, New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
Yasuhiro
Y
Maejima
Jonathan
J
Galeotti
Jeffery D
JD
Molkentin
Junichi
J
Sadoshima
Peiyong
P
Zhai
D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006439:Hemodynamics / Q000502:physiology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017725:Ventricular Pressure / Q000502:physiology
D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse