Angiotensin II activates AMPK for execution of apoptosis through energy-dependent and -independent mechanisms

作者：Day Regina M^*; Lee Young H; Han Li; Kim Yong Chul; Feng Ying Hong

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2011, 301(5): L772-L781.

DOI：10.1152/ajplung.00072.2011

• AMP-dependent kinase
• Src-homology two-domain-containing phosphatase-2
• Bcl-x(L)
• endothelial cells
• G protein-coupled receptor

Day RM, Lee YH, Han L, Kim Y-C, Feng Y-H. Angiotensin II activates AMPK for execution of apoptosis through energy-dependent and -independent mechanisms. Am J Physiol Lung Cell Mol Physiol 301: L772-L781, 2011. First published August 19, 2011; doi:10.1152/ajplung.00072.2011.-At the cellular level, 5'-AMP-activated protein kinase (AMPK) serves as a critical link between energy homeostasis and the regulation of fundamental biological activities, including apoptosis. Angiotensin (Ang) II plays a key role in fibrotic lung remodeling. We recently demonstrated that Ang II induces apoptosis in pulmonary artery endothelial cells (PAEC) through the Ang type 2 receptor (AT(2)). AT(2) activates Src-homology two-domain-containing phosphatase-2 (SHP-2) in a signaling cascade leading to Bcl-x(L) mRNA destabilization and initiation of intrinsic apoptosis. We investigated the requirement of AMPK and ATP generation for Ang II-induced apoptosis in PAEC. Ang II activated AMPK, which was required for ATP generation. Inhibition of ATP production by compound C, an AMPK inhibitor, or by oligomycin suppressed Ang II-induced apoptosis. Experiments in Chinese hamster ovary-K1 cells expressing ectopic AT(2) (wild-type, mutant D90A, or carboxy terminal truncated mutant tC319) demonstrated that AT(2) activation of AMPK required the active conformation of the receptor and the carboxy terminal 44 amino acids. AMPK associated with and activated SHP-2 and was required for Bcl-x(L) mRNA destabilization. These are the first findings demonstrating that AMPK is activated by Ang II to produce ATP required for apoptosis. Our data also indicate that AMPK plays an energy-independent role by mediating SHP-2 activation.

• 出版日期2011-11