The endothelium-derived contracting factor uridine adenosine tetraphosphate induces P2Y2-mediated pro-inflammatory signaling by monocyte chemoattractant protein-1 formation

Abstract

It is very well established that purinergic signaling plays a relevant role in vascular physiology and pathophysiology. Recently, a new purinoceptor agonist uridine adenosine tetraphosphate (Up(4)A) has been identified as a highly potent endothelial-derived contracting factor (EDCF). The purpose of the study was to investigate Up(4)A's influence on pro-inflammatory mechanisms. An early component of the inflammatory response in atherogenesis is the oxidative stress-induced formation of monocyte chemoattractant protein-1 (MCP-1). Here, we investigated the influence of Up(4)A on MCP-1 formation and characterized the underlying signaling transduction mechanisms in rat vascular smooth muscle cells (VSMCs). Up(4)A induced MCP-1 expression and secretion in VSMCs via the activation of P2Y(2) in a concentration-dependent manner. MCP-1 formation depends on generation of reactive oxygen species (ROS). To determine whether the predominant source of ROS in the vasculature, the NAD(P)H oxidase (Nox), is involved, we used different approaches. The ROS scavenger, tiron, the Nox inhibitor, apocynin and diphenyl-iodonium, as well as Nox1 knockdown, diminished the Up(4)A-induced MCP-1 formation. Rac1 activation and p47(phox) translocation from cytosol to the plasma membrane-both required for assembling and activation of Nox, were stimulated by Up(4)A. ERK1/2 and p38 activation is essential for the intracellular signal transduction. In summary, Up(4)A induced Nox1-dependent ROS generation, which further stimulated MCP-1 formation via MAPK phosphorylation in VSMCs. This process requires the activation of the G-protein coupled receptor P2Y(2). Therefore, Up(4)A is not only a potent EDCF but also a potent inductor of pro-inflammatory response in the vascular wall.

Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut

“…In porcine coronary artery Up4A causes vasodilatation via adenosine (P1) receptors (9). Furthermore, Up4A causes vascular smooth muscle cell proliferation and migration (10), stimulates monocyte and lymphocyte oxidative burst activities (11), is a potent proinflammatory agent in the vascular wall (12), and may contribute to the proinflammatory status in patients with chronic kidney disease (11). Plasma of healthy human subjects contains ∼50 nmol/L Up4A, which is sufficient to elicit vascular effects (1).…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…ATP and UTP are chemotactic for dendritic cells via the P2Y 2 receptor and can attract inflammatory cells to the atherosclerotic plaque (Idzko et al, 2002). Up 4 A has been reported to be a potent mediator of pro-inflammatory responses in the atherosclerotic vascular wall involving Nox1-dependent ROS activation via P2Y 2 receptors (Schuchardt et al, 2011).…”

Diabetes and Age-Related Differences in Vascular Function of Renal Artery: Possible Involvement of Endoplasmic Reticulum Stress

“…Up 4 A plays an important role in regulation of the vascular function in physiological and pathophysiological states. [27][28][29][30] We were the first to demonstrate regional differences in Up 4 A-mediated contractions of arteries in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. 31,32 5 Furthermore, we observed enhanced Up 4 A-induced contraction in renal arteries from type 2 diabetic Goto-Kakizaki (GK) rats via increased COX/thromboxane-prostanoid (TP) receptor signaling.…”