Biomedical subjects

U R Schwarz

Publications and source records attributed to U R Schwarz.

3 recordsLinked to original sources

PubMed2001

Taming platelets with cyclic nucleotides.

Cardiovascular diseases are often accompanied and aggravated by pathologic platelet activation. Tight regulation of platelet function is an essential prerequisite for intact vessel physiology or effective cardiovascular therapy. Physiological platelet antagonists as well as various pharmacological vasodilators inhibit platelet function by activating adenylyl and guanylyl cyclases and increasing intracellular cyclic AMP (cAMP) and cyclic GMP (cGMP) levels, respectively. Elevation of platelet cyclic nucleotides interferes with basically all known platelet activatory signaling pathways, and effectively blocks complex intracellular signaling networks, cytoskeletal rearrangements, fibrinogen receptor activation, degranulation, and expression of pro-inflammatory signaling molecules. The major target molecules of cyclic nucleotides in platelets are cyclic nucleotide-dependent protein kinases that mediate their effects through phosphorylation of specific substrates. They directly affect receptor/G-protein activation and interfere with a variety of signal transduction pathways, including the phospholipase C, protein kinase C, and mitogen-activated protein kinase pathways. Regulation of these pathways blocks several steps of cytosolic Ca(2+) elevation and controls a multitude of cytoskeleton-associated proteins that are directly involved in organization of the platelet cytoskeleton. Due to their multiple sites of action and strong inhibitory potencies, cyclic nucleotides and their regulatory pathways are of particular interest for developing new approaches for the treatment of thrombotic and cardiovascular disorders.

Adenylyl Cyclases↗

PubMed2000

Inhibition of agonist-induced p42 and p38 mitogen-activated protein kinase phosphorylation and CD40 ligand/P-selectin expression by cyclic nucleotide-regulated pathways in human platelets.

Platelet activation and adhesion to endothelial cells and extracellular matrix proteins are crucial events in the development of arterial cardiovascular diseases. Platelet activation is initiated by stimulation of intracellular signaling cascades, including the p42 mitogen-activated protein kinase (MAPK) and p38 MAPK pathways, followed by major changes in the platelet cytoskeleton and expression and activation of platelet surface receptors, such as P-selectin (CD62P) and CD40 ligand (CD40L). Activated platelets directly bind to vascular endothelial cells via CD40L/CD40 interactions and induce inflammatory reactions that initiate or aggravate atherosclerotic lesions. The aim of this study was to investigate effects of two known platelet inhibitors-the cAMP-elevating prostaglandin E(1) (PG-E(1)) and the cGMP-elevating sodium nitroprusside (SNP)-on platelet p42 MAPK and p38 MAPK activation as well as on surface expression of CD62P and CD40L. MAPK activation was analyzed by Western blot experiments using phosphorylation-specific antibodies, and surface CD40L and CD62P expression was determined by flow cytometry analysis. PG-E(1) and SNP strongly inhibited p42 and p38 MAPK phosphorylation as well as CD40L and CD62P expression in response to thrombin, a thromboxane A(2) analog, and ADP. These data indicate that adenosine and guanosine 3',5'-cyclic monophosphate-dependent protein kinases not only inhibit platelet pathways leading to activation and aggregation, but also those resulting in enhanced surface expression of protein ligands involved in inflammation. Expression of CD40L and CD62P was found to be independent of MAPK activation, since it was not inhibited by specific MAPK inhibitors. Inhibition of platelet-induced inflammatory responses including CD62P- and CD40L-mediated interaction of platelets with leukocytes and endothelial cells, respectively, is suggested to be an important component of the long-term vasoprotective effects of cyclic nucleotide-elevating prostaglandins and NO donors.

Alprostadil↗

PubMed1999

Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets--definition and detection of ticlopidine/clopidogrel effects.

Increased platelet adhesion or aggregation are key events in the pathogenesis of cardiovascular diseases. Exact determination of the platelet activation state is essential to recognize, prevent, and treat cardiovascular complications due to platelet dysfunction. Initial phases of platelet activation and inhibition are characterized by phosphorylation of specific intracellular proteins. However, methodological problems often prevent analysis of platelet protein phosphorylation under clinical conditions. A novel flow cytometry-based method using a phosphorylation-specific antibody was developed for fast and easy quantification of the phosphorylation state of a specific intracellular platelet protein. This method was used to analyze various platelet receptors and their intracellular signaling which may be impaired in genetic or acquired disorders or altered due to therapeutic interventions. In a first clinical application, the inhibitory effects of ticlopidine and clopidogrel on the platelet P2YAC ADP receptor were monitored.

Adult↗