title: Estrogen Activates AMP-Activated Protein Kinase in Human Endothelial Cells via ERβ/Ca(2+)/Calmodulin-Dependent Protein Kinase Kinase β Pathway.
abstract: 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.
authors.affiliation: Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China.
authors.forename: Songbai
authors.initials: S
authors.lastname: Yang
authors.affiliation: School of Life Sciences, Jilin Agricultural University, 2888 Xincheng Street, Changchun, 130118, People's Republic of China. jingchinw@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D053644:Naphthalimides / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D001562:Benzimidazoles; D047629:Estrogen Receptor beta; D004967:Estrogens; D053644:Naphthalimides; D047428:Protein Kinase Inhibitors; C458525:STO 609; D004958:Estradiol; D052250:Nitric Oxide Synthase Type III; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase
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)