Constitutively active MEK1 rescues cardiac dysfunction caused by over expressed GSK-3α during aging and hemodynamic pressure overload

Yasuhiro Maejima, Jonathan Galeotti, Jeffery D. Molkentin, Junichi Sadoshima, Peiyong Zhai

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Expression of GSK-3α is increased in aging hearts and those subjected to hemodynamic overload. Over expressed GSK-3 α 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 over expressed GSK-3ct using constitutively active MEK1 (CA-MEK1)/GSK-3α bigenic mice (bigenic mice), which were obtained by crossing cardiac-specific GSK-3a 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 over expression in cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)H979-H988
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume303
Issue number8
DOIs
StatePublished - Oct 15 2012

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Keywords

  • Apoptosis
  • Cardiac hypertrophy
  • Signal transduction

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