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Estrogen Activates AMP-Activated Protein Kinase in Human Endothelial Cells via ERβ/Ca(2+)/Calmodulin-Dependent

Songbai Yang1, Jing Wang2

  • 1Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China.

Cell Biochemistry and Biophysics
|January 25, 2015
PubMed

Insights

Estradiol (E2) activates AMP-activated protein kinase (AMPK) in endothelial cells through estrogen receptor-beta (ERβ) and a calcium-dependent pathway involving CaMKKβ. This mechanism regulates key AMPK targets like ACC and eNOS.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cellular Metabolism

Background:

  • Estrogen is known to inhibit cytokine-induced VCAM-1 and ICAM-1 expression in endothelial cells.
  • AMP-activated protein kinase (AMPK) acts as a cellular energy sensor, regulated by kinases like CaMKKβ and LKB1.
  • Estrogen receptor-beta (ERβ) plays a role in cellular signaling pathways.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which estrogen activates AMPK in human endothelial cells.
  • To identify the specific upstream kinase responsible for estrogen-mediated AMPK activation.
  • To investigate the role of calcium signaling in estrogen-induced AMPK activation.

Main Methods:

  • Utilized human endothelial cells in culture.
  • Employed estradiol (E2) stimulation to activate estrogen receptors.
  • Used specific inhibitors (STO-609) and gene down-regulation to probe kinase involvement (CaMKKβ, LKB1).
  • Assessed AMPK activation via phosphorylation of its targets, acetyl coenzyme A carboxylase (ACC) and endothelial nitric oxide synthase (eNOS).

Main Results:

  • Estradiol (E2) activated AMPK through a calcium-dependent mechanism involving estrogen receptor-beta (ERβ).
  • Inhibition of CaMKK (CaMKKα/β) attenuated E2-induced AMPK activation, implicating CaMKKβ.
  • Down-regulation of LKB1 did not affect E2-induced AMPK activation.
  • E2 stimulation led to phosphorylation of ACC and eNOS, which was abolished by CaMKKβ inhibition.
  • Ca(2+) was identified as a key regulator in E2-stimulated AMPK activation.

Conclusions:

  • Estradiol (E2) activates AMPK in endothelial cells via an ERβ/Ca(2+)/CaMKKβ-dependent pathway.
  • CaMKKβ is the primary kinase mediating E2-induced AMPK activation in this context.
  • Calcium signaling is crucial for the estrogen-mediated activation of AMPK and its downstream targets.
Keywords:
AMP-activated protein kinase (AMPK)Acetyl coenzyme A carboxylase (ACC)Calmodulin-dependent protein kinase kinase β (CaMKKβ)Endothelial nitric oxide synthase (eNOS)Estradiol (E2)Estrogen receptor-β (ERβ)

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