Phosphoinositide 3-kinases and their role in inflammation: potential clinical targets in atherosclerosis?

Inflammation has a central role in the pathogenesis of atherosclerosis at various stages of the disease. Therefore it appears of great interest to develop novel and innovative drugs targeting inflammatory proteins for the treatment of atherosclerosis. The PI3K (phosphoinositide 3-kinase) family, which catalyses the phosphorylation of the 3-OH position of phosphoinositides and generates phospholipids, controls a wide variety of intracellular signalling pathways.

Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes.

Background: The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-gamma (PI3Kgamma) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3Kgamma in the cardiovascular system suggest that PI3Kgamma plays a role in atherosclerosis.

Stimulation of phosphoinositide kinases by thrombin is restricted to the plasma membrane in platelets.

This study was based on the hypothesis that lipid kinases in the different subcellular fractions would be differently affected by thrombin-treatment of platelets prior to subcellular fractionation. When using our previously reported method for subcellular fractionation on Percoll self-generated gradients, marker enzymes were detected as previously described. Stimulation of intact platelets with thrombin induced increased activities of PtdIns 4-kinase, PtdIns(4)P 5-kinase and PtdIns(4,5)P(2) 3-kinase in the plasma membrane fraction.

Selective activation of nuclear phospholipase D-1 by g protein-coupled receptor agonists in vascular smooth muscle cells.

Recent studies highlight the existence of an autonomous nuclear lipid metabolism related to cellular proliferation. However, the importance of nuclear phosphatidylcholine (PC) metabolism is poorly understood. Therefore, we were interested in nuclear PCs as a source of second messengers and, particularly, nuclear phospholipase D (PLD) identification in membrane-free nuclei isolated from pig aorta vascular smooth muscle cells (VSMCs).

Nuclear Ptdlns(3,4,5)P3 signaling: an ongoing story.

Phosphatidylinositol 3,4,5-trisphosphate (Ptdlns(3,4,5)P(3)) is linked to a variety of cellular functions, such as growth, cell survival, and differentiation. Ptdlns(3,4,5)P(3) is primarily synthesized by class I phosphoinositide 3-kinases and its hydrolysis by two 3-phosphoinositide 3-phosphatases, PTEN and SHIP proteins, leads to the production of two other second messengers, Ptdlns(4,5)P(2) and Ptdlns(3,4)P(2), respectively. Evidence accumulated over the last years strongly suggest that Ptdlns(3,4,5)P(3) is an important component of signaling pathway operating within the nucleus.