Inhibitory mechanisms of very low-dose rivaroxaban in non-ST-elevation myocardial infarction.

Very low-dose (VLD) factor Xa (FXa) inhibition, in combination with acetylsalicylic acid (ASA) and clopidogrel, is associated with improved outcomes in patients with acute coronary syndrome (ACS) with a tolerable bleeding risk profile. To date, there are no data documenting platelet inhibition and the anticoagulatory effects of VLD FXa inhibition on top of guideline-adherent dual-antiplatelet therapy (DAPT) in patients with ACS. Patients with non-ST-elevation myocardial infarction (NSTEMI) receiving oral DAPT (ASA + clopidogrel, n = 20; or ASA + ticagrelor, n = 20) were prospectively enrolled in a nonrandomized study.

Tetraspanin CD9 regulates cell contraction and actin arrangement via RhoA in human vascular smooth muscle cells.

The most prevalent cardiovascular diseases arise from alterations in vascular smooth muscle cell (VSMC) morphology and function. Tetraspanin CD9 has been previously implicated in regulating vascular pathologies; however, insight into how CD9 may regulate adverse VSMC phenotypes has not been provided. We utilized a human model of aortic smooth muscle cells to understand the consequences of CD9 deficiency on VSMC phenotypes.

Pro-MMP-9 upregulation in HT1080 cells expressing CD9 is regulated by epidermal growth factor receptor.

Degradation of the surrounding extracellular matrix (ECM) by matrix metalloproteinases (MMPs) drives invasion and metastasis of cancer cells. We previously demonstrated that tetraspanin CD9 expression upregulates pro-MMP-9 expression and release and promotes cellular invasion in a human fibrosarcoma cell line (HT1080). These events were dependent upon the highly functional second extracellular loop of CD9.

Tetraspanin CD9 promotes the invasive phenotype of human fibrosarcoma cells via upregulation of matrix metalloproteinase-9.

Tumor cell metastasis, a process which increases the morbidity and mortality of cancer patients, is highly dependent upon matrix metalloproteinase (MMP) production. Small molecule inhibitors of MMPs have proven unsuccessful at reducing tumor cell invasion in vivo. Therefore, finding an alternative approach to regulate MMP is an important endeavor.

Detergent and detergent-free methods to define lipid rafts and caveolae.

Lipid rafts and their related membrane vesicular structures, caveolae, are cholesterol- and sphingolipid-rich microdomains of the plasma membrane that have attracted considerable interest because of their ability to concentrate numerous signaling proteins. Efforts to define the proteins that reside in lipid rafts and caveolae as well as investigations into the functional role of these microdomains in signaling, endocytosis, and other cellular processes have led to the hypothesis that they compartmentalize or prearrange molecules involved in regulating these pathways. This chapter describes biochemical approaches for defining lipid rafts and caveolae.

cAMP inhibits transforming growth factor-beta-stimulated collagen synthesis via inhibition of extracellular signal-regulated kinase 1/2 and Smad signaling in cardiac fibroblasts.

Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Cytokines such as transforming growth factor-beta (TGF-beta) play a fundamental role in the development of tissue fibrosis by stimulating matrix deposition and other profibrotic responses, but less is known about pathways that might inhibit fibrosis. Increased cAMP formation inhibits myofibroblast differentiation and collagen production by cardiac fibroblasts, but the mechanism of this inhibition is not known.

Methods for the study of signaling molecules in membrane lipid rafts and caveolae.

Lipid rafts and caveolae are cholesterol- and sphingolipid-rich microdomains of the plasma membrane that concentrate components of certain signal transduction pathways. Interest in and exploration of these microdomains has grown in recent years, especially after the discovery of the biochemical marker of caveolae, caveolin, and the recognition that caveolin interacts with many different signaling molecules via its scaffolding domain. There are three major types of caveolins (1, 2, and 3), with some selectivity in their expression in different tissues.

The use of the point of care Helena ICHOR/Plateletworks and the Accumetrics Ultegra RPFA for assessment of platelet function with GPIIB-IIIa antagonists.

Objective: To evaluate a newly modified rapid platelet function analysis system (ICHOR/ Plateletworks) and to compare the results obtained with those of traditional light transmission aggregometry (LTA), and the Ultegra/RPFA system.

Background: Anti-platelet therapy is standard of care for patients as an adjunct to percutaneous coronary intervention (PCI) or for medical management of non-ST elevation acute coronary syndromes (NSTE ACS). Recent clinical trial results suggest that the three currently approved platelet GPIIb-IIIa receptor antagonists, eptifibatide, tirofiban and abciximab, may vary in extent of inhibition of platelet aggregation (IPA) at the approved doses.

Molecular biological approaches to unravel adenylyl cyclase signaling and function.

Signal transduction through the cell membrane requires the participation of one or more plasma membrane proteins. For many transmembrane signaling events adenylyl cyclases (ACs) are the final effector enzymes which integrate and interpret divergent signals from different pathways. The enzymatic activity of adenylyl cyclases is stimulated or inhibited in response to the activation of a large number of receptors in virtually all cells of the human body.

The C terminus of sprouty is important for modulation of cellular migration and proliferation.

The Drosophila Sprouty (SPRY) protein has been shown to inhibit the actions of epidermal growth factor and fibroblast growth factor. However, the role of mammalian SPRY proteins has not been clearly elucidated. We postulated that human Sprouty2 (hSPRY2) is an inhibitor of cellular migration and proliferation.