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

Abstract

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 (AT2). AT2 activates Src-homology two-domain-containing phosphatase-2 (SHP-2) in a signaling cascade leading to Bcl-xL 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 AT2 (wild-type, mutant D90A, or carboxy terminal truncated mutant tC319) demonstrated that AT2 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-xL 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.