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

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

Cell Biochemistry and Biophysics 72(3): 701-707

Our previous studies suggested that Estrogen inhibits cytokine-induced expression of VCAM-1 and ICAM-1 in cultured human endothelial cells via AMP-activated protein kinase (AMPK) activation. Here, we sought to delineate the mechanisms underlying estrogen activation of AMPK. AMPK can be considered a 'fuel gauge' of cellular energy status in response to metabolic stress. It is controlled by upstream kinases such as Ca(2+)/calmodulin-dependent protein kinase kinase β (CaMKKβ) or LKB1. The present study of human endothelial cells demonstrates that AMPK is activated by estradiol (E2) through a Ca(2+)-dependent mechanism involving the estrogen receptor-β (ERβ) activation. Inhibition of CaMKK with STO-609, a specific inhibitor of CaMKKα and CaMKKβ, attenuated E2-induced AMPK activation, suggesting that CaMKKβ was the responsible AMPK kinase. Conversely, down-regulation of LKB1 did not affect E2-induced AMPK activation. E2 stimulation caused phosphorylation of acetyl coenzyme A carboxylase (ACC) and endothelial nitric oxide synthase (eNOS), two main targets of AMPK. Inhibition or down-regulation of CaMKKβ eliminated phosphorylation of ACC and eNOS in response to E2. Together, our data highlight the role of Ca(2+) as a regulator of AMPK activation in response to E2 stimulation. We demonstrate that E2 activates AMPK via an ERβ/Ca(2+)/CaMKKβ-dependent pathway in endothelial cells.

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Accession: 057800038

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PMID: 25616441

DOI: 10.1007/s12013-015-0521-z

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