Beta-catenin downregulation is required for adaptive cardiac remodeling.

The armadillo-related protein beta-catenin has multiple functions in cardiac tissue homeostasis: stabilization of beta-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell-cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of beta-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II).

Requirement of nuclear factor-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo.

Background: In vitro experiments have proposed a role of nuclear factor-kappaB (NF-kappaB), a transcription factor, in cardiomyocyte hypertrophy and protection against apoptosis. Currently, the net effect on cardiac remodeling in vivo under common stress stimuli is unclear.

Methods And Results: We have generated mice with cardiomyocyte-restricted expression of the NF-kappaB super-repressor IkappaBalphaDeltaN (DeltaN(MHC)) using the Cre/lox technique.

Differential regulation and relocalization of the platelet P2Y receptors after activation: a way to avoid loss of hemostatic properties?

In the present study, we investigated the desensitization and trafficking of the P2Y1 and P2Y12 receptors after agonist-induced stimulation of platelets or astrocytoma cells transfected with the P2Y1 or P2Y12 receptors fused to green fluorescent protein. In platelets and in transfected cells, exposure to 10 microM ADP caused desensitization of the P2Y1 receptor-driven calcium signal, whereas the P2Y12 receptor-mediated inhibition of cAMP formation was not affected. Plasma membranes from ADP-stimulated platelets also retained P2Y12 activity.

Statins inhibit reoxygenation-induced cardiomyocyte apoptosis: role for glycogen synthase kinase 3beta and transcription factor beta-catenin.

Background: Statins may improve left ventricular remodeling after myocardial infarction. We tested whether statins inhibit cardiomyocyte apoptosis through glycogen synthase kinase 3beta (GSK3beta) inactivation and evaluated activation of downstream transcription factors.

Methods/results: Mevastatin and pravastatin activated serine/threonine kinase Akt in neonatal cardiomyocytes dose and time dependently with maximal activation at 15 min/10 microM.

Synthesis and biological activity of 2-alkylated deoxyadenosine bisphosphate derivatives as P2Y(1) receptor antagonists.

A previous study around adenine nucleotides afforded the reference N(6)-methyl-2'-deoxyadenosine-3',5'-bisphosphate (1a, MRS 2179) as a selective human P2Y(1) receptor antagonist (pA(2)=6.55+/-0.05) with antithrombotic properties.

The P2Y(1) receptor as a target for new antithrombotic drugs: a review of the P2Y(1) antagonist MRS-2179.

MRS-2179 is a selective P2Y(1) receptor antagonist, a strong inhibitor of ADP-induced platelet aggregation in vitro and ex vivo. By i.v.

A general approach toward the synthesis of C-nucleoside pyrazolo[1,5-a]-1,3,5-triazines and their 3',5'-bisphosphate C-nucleotide analogues as the first reported in vivo stable P2Y(1)-receptor antagonists.

In our effort to identify potent purinergic P2Y(1) receptor antagonists as potent platelet aggregation inhibitors with enhanced metabolic stability, we developed an efficient route for the large-scale preparation of 2'-deoxy-C-nucleosides of pyrazolo[1,5-a]-1,3,5-triazine. The key strategic elements of this novel synthetic approach involved the following: (i) the use of a novel activating group, the N-methyl-N-phenylamino group, which was easily generated in high yield by treatment of the pyrazolo[1,5-a]-1,3,5-triazin-4-one (5) with phosphorus oxychloride and dimethylaniline under high pressure, (ii) a regio- and stereospecific palladium-mediated coupling reaction of the readily available unprotected glycal 1,4-anhydro-2-deoxy-D-erythro-pent-1-enitol (4b) and the 8-iodo derivative (16), and (iii) the stereoselective reduction of the ketone group of the furanosyl ring followed by the subsequent displacement of the N-methyl-N-phenylamino group upon treatment with methylamine. The beta configuration at the anomeric C-1' position of the glycal moieties was perfectly retained throughout this conversion.

Novel antagonists acting at the P2Y(1) purinergic receptor: synthesis and conformational analysis using potentiometric and nuclear magnetic resonance titration techniques.

The human P2Y(1) receptor is widely distributed in many tissues and has a classical structure of a G protein-coupled receptor. Activated by adenosine-5'-diphosphate (ADP), this receptor is essential for platelet aggregation. In the present paper, we describe the synthesis of novel P2Y(1) antagonists that could be of interest at least as tools to define the physiological roles of the P2Y(1) receptor, at best as new antithrombotic agents.