Administration of MR16-1 after MI suppressed myocardial inflammation, resulting in the amelioration of LV remodelling. Neutralization of the IL-6 receptor is a potentially useful strategy for protecting hearts from LV remodelling after MI.

BackgroundMetabolic disorders, caused by excessive calorie intake and low physical activity, are important cardiovascular risk factors. Rho-kinase, an effector protein of the small GTP-binding protein RhoA, is an important cardiovascular therapeutic target and its activity is increased in patients with metabolic syndrome. We aimed to examine whether Rho-kinase inhibition improves high-fat diet (HFD)-induced metabolic disorders, and if so, to elucidate the involvement of AMP-activated kinase (AMPK), a key molecule of metabolic conditions.Methods and ResultsMice were fed a high-fat diet, which induced metabolic phenotypes, such as obesity, hypercholesterolemia and glucose intolerance. These phenotypes are suppressed by treatment with selective Rho-kinase inhibitor, associated with increased whole body O2 consumption and AMPK activation in the skeletal muscle and liver. Moreover, Rho-kinase inhibition increased mRNA expression of the molecules linked to fatty acid oxidation, mitochondrial energy production and glucose metabolism, all of which are known as targets of AMPK in those tissues. In systemic overexpression of dominant-negative Rho-kinase mice, body weight, serum lipid levels and glucose metabolism were improved compared with littermate control mice. Furthermore, in AMPKα2-deficient mice, the beneficial effects of fasudil, a Rho-kinase inhibitor, on body weight, hypercholesterolemia, mRNA expression of the AMPK targets and increase of whole body O2 consumption were absent, whereas glucose metabolism was restored by fasudil to the level in wild-type mice. In cultured mouse myocytes, pharmacological and genetic inhibition of Rho-kinase increased AMPK activity through liver kinase b1 (LKB1), with up-regulation of its targets, which effects were abolished by an AMPK inhibitor, compound C.ConclusionsThese results indicate that Rho-kinase inhibition ameliorates metabolic disorders through activation of the LKB1/AMPK pathway, suggesting that Rho-kinase is also a novel therapeutic target of metabolic disorders.

Objective— Vascular endothelium plays an important role to maintain cardiovascular homeostasis through several mechanisms, including endothelium-dependent hyperpolarization (EDH). We have recently demonstrated that EDH is involved in endothelial metabolic regulation in mice. However, it remains to be examined whether AMP-activated protein kinase (AMPK), an important metabolic regulator, is involved in EDH and if so, whether endothelial AMPK (eAMPK) plays a role for circulatory regulation. Approach and Results— We examined the role of eAMPK in EDH, using mice with endothelium-specific deficiency of α-catalytic subunit of AMPK, either α 1 (eAMPKα 1 −/− α 2 +/+ ) or α 2 (eAMPKα 1 +/+ α 2 −/− ) alone or both of them (eAMPKα 1 −/− α 2 −/− ). We performed telemetry, organ chamber, electrophysiological, and Langendorff experiments to examine blood pressure, vascular responses, hyperpolarization of membrane potential, and coronary flow responses, respectively. Hypertension was noted throughout the day in eAMPKα 1 −/− α 2 −/− and eAMPKα 1 −/− α 2 +/+ but not in eAMPKα 1 +/+ α 2 −/− mice when compared with respective control. Importantly, endothelium-dependent relaxations, EDH, and coronary flow increase were all significantly reduced in eAMPKα 1 −/− α 2 −/− and eAMPKα 1 −/− α 2 +/+ but not in eAMPKα 1 +/+ α 2 −/− mice. In contrast, endothelium-independent relaxations to sodium nitroprusside (a NO donor), NS-1619 (a Ca 2+ -activated K + channel opener), and exogenous H 2 O 2 were almost comparable among the groups. In eAMPKα 1 −/− α 2 −/− mice, antihypertensive treatment with hydralazine or long-term treatment with metformin (a stimulator of AMPK) failed to restore EDH-mediated responses. Conclusions— These results provide the first direct evidence that α 1 subunit of eAMPK substantially mediates EDH responses of microvessels and regulates blood pressure and coronary flow responses in mice in vivo, demonstrating the novel role of eAMPK in cardiovascular homeostasis.

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In this paper we report two new PEM fuel cell catalyst durability test results using 3M's nanostructured thin film (NSTF) catalysts, which do not use carbon-supports or additional ionomer in the electrode layer. One test uses an automotive start/stop (S/S) testing protocol provided through communication with Nissan, and compares the NSTF catalyst durability with that of a conventional carbon supported dispersed Pt catalyst. Fuel cell performance, cyclic voltammograms, surface area changes, specific activity (900mV 150kPa H 2 /O 2 , saturated) and XRD crystallite sizes were measured before and after S/S testing. The NSTF catalyst show much less loss of performance under the S/S cycling and most of the loss is recoverable. The second test involves high current density operation under totally dry H 2 /O 2 conditions. Operating with an average current density of 1 A/cm 2 , with over 1600 scans between 0.1 and 2 A/cm 2 , the NSTF MEA lasted 1000 hours, consistent with extremely low measured fluoride ion emission rates.

To explore the connection between α-(BEDT−TTF) 2 I 3 and α-(BEDT−TTF) 2 MHg(SCN) 4 (M = K, Rb, Tl and NH 4 ) and to resolve the difference between band picture and charge fluctuation of α-(BEDT−TTF) 2 MHg(SCN) 4 , we utilized 13 C-NMR to examine α-(BEDT−TTF) 2 RbHg(SCN) 4 under the conditions with a large hyperfine coupling constant at each site. The temperature dependence of site susceptibility showed the development of spin disproportionation as observed in α-(BEDT−TTF) 2 I 3 . We found that the linewidth of the A site only increased as temperature decreased from 200 to 100 K, a change associated with the development of lattice modulation. These findings indicate that density-wave modulation occurs during charge disproportionation instability.

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