Natriuretic peptides enhance adiponectin production by human adipocytes in vitro and even in patients with CHF, which might have a beneficial effect on cardiomyocytes in patients receiving recombinant natriuretic peptide therapy for heart failure.

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Lipid rafts have attracted much attention because of their significant functional roles in membrane-associated processes. It is thought that sphingomyelin and cholesterol are essential for forming lipid rafts; however, their motion characteristics are not fully understood despite numerous studies. Here we show accurate local motions encompassing an entire sphingomyelin molecule, which were captured by measuring quadrupole splittings for 19 kinds of site-specifically deuterated sphingomyelins (that is, molecular motion capture of sphingomyelin). The quadrupole splitting profiles, which are distinct from those reported from perdeuterated sphingomyelins or simulation studies, reveal that cholesterol enhances the order in the middle parts of the alkyl chains more efficaciously than at the shallow positions. Comparison with dimyristoylphosphocholine bilayers suggests that cholesterol is deeper in sphingomyelin bilayers, which likely explains the so-called umbrella effect. The experiments also demonstrate that (i) the C2'-C3' bond predominantly takes the gauche conformation, (ii) the net ordering effect of cholesterol in sphingomyelin bilayers is not larger than that in phosphatidylcholine bilayers, (iii) cholesterol has no specific preference for the acyl or sphingosine chain, (iv) the acyl and sphingosine chains seem mismatched by about two methylene lengths, and (v) the motion of the upper regions of sphingomyelin chains is less temperature dependent than that of lower regions probably due to intermolecular hydrogen bond formation among SM molecules. These insights into the atomic-level dynamics of sphingomyelin provide critical clues to understanding the mechanism of raft formation.

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Background-Adenosine inhibits proliferation of cardiac fibroblasts and hypertrophy of cardiomyocytes, both of which may play crucial roles in cardiac remodeling. In the present study, we investigated whether chronic stimulation of adenosine receptors begun after myocardial infarction (MI) prevents cardiac remodeling. Methods and Results-MI was produced in Wistar rats by permanent ligation of the left anterior descending coronary artery. One week after the onset of MI, animals were randomized into 8 groups: vehicle, dipyridamole (DIP; the adenosine uptake inhibitor, 50 mg/kg), 2-chroloadenosine (CADO; the stable analogue of adenosine, 2 mg/kg), and CADO in the presence of the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (8-SPT) or the selective antagonist for adenosine A1, A2a, A2b, or A3 receptor. Three weeks after treatment, hemodynamic and echocardiographic parameters in the DIP and CADO groups were significantly improved compared with the vehicle group. These hemodynamic and echocardiographic improvements were blunted by either 8-SPT or the selective adenosine A2b antagonist MRS1754 but not by the selective antagonists for other subtypes of adenosine receptors. The collagen volume fraction was smaller, and gene expression of the molecules associated with cardiac remodeling such as matrix metalloproteinase in noninfarcted areas was reduced in the DIP and CADO groups compared with the vehicle group, both of which were attenuated by either 8-SPT or MRS1754. Conclusions-Long-term

Prostaglandins (PGs) are multi-potent mediators for local tissue homeostasis and inflammatory reactions. Addition of PGs to cultures of human skin fibroblasts led to a marked induction of the production of hepatocyte growth factor (HGF). PGE1 and PGI2 analogues were the most potent in stimulating HGF production by over 50-fold; PGE2 and PGD2 were less potent. Western immunoblotting of conditioned medium from skin fibroblasts indicated that both PGE1, PGE2, and PGI2 analogues specifically induce synthesis of HGF with a M(r) of 85,000, but not smaller variant of HGF with a M(r) of 28,000. Consistent with the induction of HGF production, steady-state expression of HGF mRNA in fibroblasts was strongly induced by PGE1 and PGI2 analogues, but slightly by PGE2 and PGD2, thereby indicating that PGs induce HGF production through transcriptional activation of the HGF gene. PGE1, PGE2, PGI2 analogue also stimulated HGF production in MRC-5 human embryonic lung fibroblasts and vascular smooth muscle cells. As dibutyryl cyclicAMP (dbcAMP) and tetradecanoylphorbol 13-acetate (TPA), but not Ca(2+)-ionophore A23187 stimulated HGF production in skin fibroblasts, activation of protein kinase-A and protein kinase-C may be coupled to the stimulation of HGF production. Simultaneous addition of PGE1 and TPA or dbcAMP and TPA led to a synergistic enhancement of HGF production, whereas the simultaneous addition of PGE1 and dbcAMP failed to additively enhance HGF production.(ABSTRACT TRUNCATED AT 250 WORDS)

Since the expression of genes for platelet-derived growth factor (PDGF)-A and PDGF beta-receptor are reciprocally regulated in vascular wall cells after balloon injury, we have investigated the ability of specific vasoactive molecules or growth factors to reproduce the injury pattern of gene expression in cultured rat smooth muscle cells (SMCs) and assessed the effect of inactivating alpha-thrombin on injury-induced expression of PDGF-A mRNA by vascular wall cells in vivo. The molecules investigated, to which vascular SMCs may be locally exposed after mechanical injury, included vasoactive factors (alpha- and beta-adrenergic agonists, serotonin, histamine, angiotensin II, and endothelin) and growth factors (PDGF-AA, PDGF-BB, basic fibroblast growth factor, insulin-like growth factor, epidermal growth factor, and alpha-thrombin). In cultured rat SMCs, only alpha-thrombin (0.1-100 nM), among these compounds, produced the pattern of transiently increased PDGF-A and decreased PDGF beta-receptor mRNA. PDGF-B chain mRNA levels remained undetectable in these cultured SMCs. The dependence of these changes in gene expression on the proteolytic activity of alpha-thrombin was shown by the interruption of altered gene expression or DNA synthesis after incubating the cultured SMCs with covalently inactivated alpha-thrombin using D-Phe-Pro-Arg chloromethyl ketone, a synthetic direct active-site irreversible inhibitor of alpha-thrombin. Continuous intravenous infusion of this synthetic antithrombin into baboons for 6 hours (100 nmol/kg per minute maintaining constant plasma levels of 3.0 +/- 0.5 microns/ml) after inducing balloon-catheter arterial injury also prevented the threefold increase in expression of PDGF-A mRNA characteristically exhibited by untreated mechanically injured vessels.(ABSTRACT TRUNCATED AT 250 WORDS)