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

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-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-K _L 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-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.