Activation of AMPK stimulates heme oxygenase-1 gene expression and human endothelial cell survival

作者：Liu Xiao ming; Peyton Kelly J; Shebib Ahmad R; Wang Hong; Korthuis Ronald J; Durante William^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2011, 300(1): H84-H93.

DOI：10.1152/ajpheart.00749.2010

• vascular biology
• metabolic stress
• endothelium
• AMP-activated protein kinase

Liu X, Peyton KJ, Shebib AR, Wang H, Korthuis RJ, Durante W. Activation of AMPK stimulates heme oxygenase-1 gene expression and human endothelial cell survival. Am J Physiol Heart Circ Physiol 300: H84-H93, 2011. First published October 29, 2010; doi:10.1152/ajpheart.00749.2010.-The present study determined whether AMP-activated protein kinase (AMPK) regulates heme oxygenase (HO)-1 gene expression in endothelial cells (ECs) and if HO-1 contributes to the biological actions of this kinase. Treatment of human ECs with the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) stimulated a concentration-and time-dependent increase in HO-1 protein and mRNA expression that was associated with a prominent increase in nuclear factor-erythroid 2-related factor 2 (Nrf2) protein. Induction of HO-1 was also observed in rat carotid arteries after the in vivo application of AICAR. Induction of HO-1 by AICAR was blocked by the AMPK inhibitor compound C, the adenosine kinase inhibitor 5'-iodotubercidin, and by silencing AMPK-(alpha 1/2) and was mimicked by the AMPK activator A-769662 and by infecting ECs with an adenovirus expressing constitutively active AMPK-(alpha 1). AICAR also induced a significant rise in HO-1 promoter activity that was abolished by mutating the antioxidant responsive elements of the HO-1 promoter or by the overexpression of dominant negative Nrf2. Finally, activation of AMPK inhibited cytokine-mediated EC death, and this was prevented by the HO inhibitor tin protoporphyrin-IX or by silencing HO-1 expression. In conclusion, AMPK stimulates HO-1 gene expression in human ECs via the Nrf2/antioxidant responsive element signaling pathway. The induction of HO-1 mediates the antiapoptotic effect of AMPK, and this may provide an important adaptive response to preserve EC viability during periods of metabolic stress.

• 出版日期2011-1