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

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. Diabetes 52:2381-2388, 2003 N onenzymatic glycoxidation, which ultimately leads to the formation of advanced glycation end products (AGEs), occurs when free amino groups are exposed to aldoses, such as high levels of glucose, and under conditions of oxidant stress, both of which occur in diabetes (1). AGE-modified macromolecules are found in plasma, cells, and tissues and accumulate in vessel walls and the kidney.The receptor for AGE (RAGE) is a member of the immunoglobulin superfamily of cell-surface molecules (1). As the biology of RAGE has evolved, several common themes have emerged. First, the multiligand character of the receptor is quite remarkable. Ligands of the receptor include AGEs, crossed-sheet fibrils characteristic of amyloid, amphoterin, and S100/calgranulins (1). Even within a particular ligand family, RAGE recognizes more than one species. For example, the S100/calgranulins comprise a family of Ͼ15 polypeptides. RAGE interacts with an S100a species and S100B (two rather divergent family members), raising the likely possibility that this receptor may well interact with multiple, and maybe even all, S100/calgranulins. A second salient feature of RAGE biology is the presence of more than one ligand in tissues for prolonged times (1). For example, in diabetic tissues, both AGEs and S100/calgranulins are present at increased levels in many cases. Another unusual feature of the receptor is its apparent colocalization to sites where its ligands tend to accumulate (1). Thus, where AGEs and S100/calgranulins accumulate at sites of vascular lesions, higher levels of RAGE are also identified in cellular elements. This observation raises the possibility that the presence of ligands upregulates expression of the receptor, potentially resulting in exaggerated RAGE-mediated cellular activation. This has been demonstrated directly with S100B and appears to be true with AGEs, amphoterin, and amyloids.The broad consequences of RAGE-ligand interaction for cellular properti...

Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury

“…Activation of NADPH oxidase contributed, at least in part, to enhancing oxidant stress via RAGE (52). In addition, S100B-RAGE interaction triggered intracellular generation of reactive oxygen species via activation of phospholipase D (46). Similar observations were made in diabetic rats created by STZ injection (45), the same rat model used in the present study.…”

Role of the JAK/STAT signaling pathway in diabetic nephropathy

“…Recently, our group has shown in VSMC that 1) the RAGE ligand S100B augments ANG II-induced activation of the JAK/STAT pathway; 2) S100B-RAGE interaction induces intracellular production of ROS, such as H 2 O 2 ; and 3) anti-RAGE IgG blocks S100B enhancement of ANG II-induced JAK2 tyrosine phosphorylation in VSMC. Moreover, we also found that PKC-␤ inhibition blocks S100B-induced production of H 2 O 2 and that PLD modulation blocks S100B augmentation of ANG II-induced JAK2 tyrosine phosphorylation (61). These data lead us to hypothesize that in kidney cells (podocytes and glomerular mesangial cells), blockade of PKC-␤ and/or PLD will decrease and/or abrogate AGE-induced H 2 O 2 production and, as a consequence, ANG II-induced activation JAK2 and STAT proteins.…”

Assessment of S100 protein expression in the epididymis of juvenile and adult European bison.

“…itive reaction for S100 protein in rat vascular smooth muscle cells [34,35], human and guinea pig smooth muscle cells from the aorta [33,36,37] and porcine isolated coronary artery smooth muscle cells [36,[38][39][40][41].…”