S100B-RAGE-Mediated Augmentation of Angiotensin II-Induced Activation of JAK2 in Vascular Smooth Muscle Cells Is Dependent on PLD2

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Abstract
Angiotensin II (Ang II), a vasoactive peptide that is also considered a growth factor, has been implicated in both normal and diabetic cellular proliferation. We recently found that activation of janus kinase 2 (JAK2) is essential for the Ang II–induced proliferation of vascular smooth muscle cells (VSMCs) and that high glucose augments Ang II–induced proliferation of VSMCs by increasing signal transduction through activation of JAK2. Here, we demonstrate that S100B, a ligand for the receptor of advanced glycation end products (RAGEs), augmented both Ang II–induced tyrosine phosphorylation of JAK2 and cell proliferation in VSMCs in a receptor-dependent manner. We also found that S100B-RAGE interaction triggered intracellular generation of reactive oxygen species (ROS), VSMC proliferation, and JAK2 tyrosine phosphorylation via activation of phospholipase D (PLD)2. These results provide direct evidence for linkages between PLD2, ROS production, and S100B-RAGE–induced enhancement of Ang II–induced cell proliferation and activation of JAK2 in VSMCs.