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Published on: June 3, 2018
Constitutively active MEK1 rescues cardiac dysfunction caused by overexpressed GSK-3α during aging and hemodynamic
Yasuhiro Maejima1, Jonathan Galeotti, Jeffery D Molkentin
1Cardiovascular 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.
Insights
Overexpression of GSK-3α in aging hearts impairs cardiac function by inhibiting the MEK1/ERK pathway. Restoring this pathway prevents GSK-3α-induced cardiac dysfunction and dysfunction.
Area of Science:
- Cardiology
- Molecular Biology
- Cellular Biology
Background:
- Glycogen synthase kinase 3-alpha (GSK-3α) is upregulated in aging and overloaded hearts, contributing to cardiac dysfunction.
- Overexpressed GSK-3α inhibits the MEK1/ERK pathway, exacerbating pressure overload-induced cardiac problems.
Purpose of the Study:
- To investigate if MEK1/ERK pathway suppression mediates GSK-3α-induced cardiac dysfunction.
- To determine the role of the MEK1/ERK pathway in the cardiac response to GSK-3α overexpression.
Main Methods:
- Generation of constitutively active MEK1 (CA-MEK1)/GSK-3α bigenic mice by crossing cardiac-specific transgenic lines.
- Assessment of cardiac function, hypertrophy, apoptosis, and fibrosis in bigenic mice, GSK-3α transgenic (Tg-GSK), CA-MEK1 transgenic (Tg-MEK1), and non-transgenic (NTg) mice.
- Evaluation of cardiac responses after applying pressure overload (PO) in these mouse models.
Main Results:
- Inhibition of ERK phosphorylation in Tg-GSK mice was reversed in bigenic mice.
- Bigenic mice showed normalized cardiac myocyte size and preserved left ventricular function compared to Tg-GSK mice.
- GSK-3α-induced cardiac dysfunction, hypertrophy suppression, and apoptosis were abrogated in bigenic mice after pressure overload.
- While fibrosis was not affected, the increase in apoptosis due to GSK-3α overexpression was abolished in bigenic mice.
Conclusions:
- Inhibition of the MEK1/ERK pathway is a key mechanism underlying GSK-3α-induced cardiac dysfunction and hypertrophy suppression.
- Restoring MEK1/ERK pathway activity can mitigate the adverse cardiac effects of GSK-3α overexpression.
Abstract:
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.
