Protection from angiotensin II–mediated vasculotoxic and hypertensive response in mice lacking PI3Kγ

Hypertension affects nearly 20% of the population in Western countries and strongly increases the risk for cardiovascular diseases. In the pathogenesis of hypertension, the vasoactive peptide of the renin-angiotensin system, angiotensin II and its G protein–coupled receptors (GPCRs), play a crucial role by eliciting reactive oxygen species (ROS) and mediating vessel contractility. Here we show that mice lacking the GPCR-activated phosphoinositide 3-kinase (PI3K)γ are protected from hypertension that is induced by administration of angiotensin II in vivo. PI3Kγ was found to play a role in angiotensin II–evoked smooth muscle contraction in two crucial, distinct signaling pathways. In response to angiotensin II, PI3Kγ was required for the activation of Rac and the subsequent triggering of ROS production. Conversely, PI3Kγ was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca2+ channel–mediated extracellular Ca2+ entry. These data indicate that PI3Kγ is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kγ function might be exploited to improve therapeutic intervention on hypertension

Gas barrier film

The invention relates to a process for the prepn. of a gas barrier film, comprising 1) providing an olefin copolymer comprising: (i) recurring units A derived from an olefin and (ii) recurring units B derived from a compd. according to formula (I)​, (II) or (III)​: (I) wherein R1 is selected from -​H or -​CH3; R2 is selected from -​0-​, -​(CO)​-​(NH)​- or -​(CO)​-​O-​; R3 is a moiety comprising 1 -​30 carbon atoms; and n is an integer between 1 and 10, (II) wherein R1 is selected from -​H or -​CH3 and p is an integer between 1 and 10, (III) wherein R1 is selected from -​H or -​CH3 and q is an integer between 1 and 10, 2) grafting a graft compd. represented by the formula (IV) or (V) to the olefin copolymer (IV) wherein R4 is independently -​H, C1 -​C10 linear, branched or cyclic alkyl; X is -​NH- or -​O- and R5 is represented by the formula: (A) where r is an integer between 1 and 20; Y is -​NCO, halogen (I, Br, CI, F)​, -​Si(OMe)​3, -​N=C=S, -​N3, -​COOH, an amino acid or an amino ester, (V) wherein each of R6, R7, R8 and R9 is independently -​H, C1 -​C10 linear, branched or cyclic alkyl; X is -​NH- or -​O- and R5 is represented by the formula: (A) where r is an integer between 1 and 20; Y is -​NCO, halogen (I, Br, CI, F)​, -​Si(OMe)​3, -​N=C=S, -​N3, -​COOH, an amino acid or an amino ester and 3) shaping the grafted polymer obtained by step 2) into a film

Stretch resistant PP film with gas barrier coating

The invention relates to a process for the preparation of an oxygen barrier film having an oxygen barrier layer and a treated substrate, comprising the steps of: a) subjecting a polyolefin substrate to a surface treatment to 5 obtain the treated substrate wherein the surface under the parts of the curves corresponding to the C-O, C-N and C=O groups is at least 10% based on the total surface under the curve as obtained by X-ray photoelectron spectroscopy (XPS), b) applying an aqueous or hydroalcoholic coating composition comprising 0.1 to 25 10 wt% of polyvinyl alcohol and 0.1 to 30 wt% of a metal alkoxide on the treated substrate obtained by step a) and c) drying the coating composition to obtain the oxygen barrier layer resulting in the oxygen barrier film

Increased basal nitric oxide release despite enhanced free radical production in hypertension

INTRODUCTION: Although in hypertension a defect in stimulated nitric oxide (NO) is well established, little is known about basal NO levels. Thus, we measured directly in vessels from normotensive [Wistar-Kyoto (WKY)] rats and spontaneously hypertensive rats (SHR) both basal and stimulated NO production using a novel technique [4,5-diaminofluorescein (DAF-2) fluorescence]. METHODS: Isolated vessels were exposed to the fluorescent probe DAF-2. After the technique was validated with increasing doses of acetylcholine in the presence and absence of NG-nitro-L-arginine methyl ester (l-NAME), we measured NO production in vessels from WKY rats and SHR in the same experimental setting. Finally, to explore the impact of reactive oxygen species (ROS) on NO release, we analysed the effect of an antioxidant, such as ascorbic acid, on basal and stimulated NO in aortic rings of WKY rats and SHR. RESULTS: Aortic rings from SHR exhibited a higher basal NO production and a lower responsiveness to agonist-induced NO release as compared with those observed in WKY rats. Also in resistance vessels such as mesenteric arteries, basal NO production was higher in hypertension. In hypertensive rats, ascorbic acid was able to further increase basal NO release and recovered the impaired stimulated NO production, whereas no effect was detected in normotensive rats. CONCLUSIONS: Our data reveal an increased basal NO availability in hypertension despite the increased production of ROS, suggesting a greater complexity in hypertensive endothelial dysfunction when the analysis is focused on direct NO measurement

Mechanisms of soluble beta-amyloid impairment of endothelial function

Alzheimer's disease ( AD) has been recently associated with vascular risk factors. beta-amyloid peptides (AbetaP), the main component of senile plaques typical of AD, circulate in soluble globular form in bloodstream. Interestingly, AbetaP is able to induce endothelial dysfunction, and this effect may represent the link between vascular and neuronal pathophysiological factors involved in AD. We aimed to clarify the molecular mechanisms underlying globular AbetaP-induced vascular toxicity. Using several methodological approaches, we have observed that in vascular tissues globular AbetaP is unable to induce oxidative stress, one of the mechanisms hypothesized involved in beta-amyloid toxicity. More important, we have demonstrated that globular AbetaP is able to localize on vascular endothelium, where it inhibits eNOS enzymatic activity. In particular, AbetaP enhances eNOS phosphorylation on threonine 495 and serine 116 and reduces acetylcholine-induced phosphorylation on serine 1177. Such an effect depends on a PKC signaling pathway, as suggested by its phosphorylation on serine 660. In fact, selective inhibition of the calcium-dependent group of PKC is able to rescue beta-amyloid-induced alteration of eNOS phosphorylation, NO production, and endothelial vasorelaxation. The activation of these Ca2+-dependent pathways is probably due to the ability of AbetaP to evoke Ca2+ leakage from inositol 1,4,5-triphosphate receptors on endoplasmic reticulum. Our data demonstrate that globular AbetaP-induced endothelial NO dysfunction can be attributed to an alteration of intracellular Ca2+ homeostasis, which could lead to the activation of calcium-dependent group of PKC with a consequent change of the eNOS phosphorylation pattern. These mechanisms could contribute to shed further light on the toxic effect of beta-amyloid in vascular tissues

The Sensory Coding of Warm Perception

Humans detect skin temperature changes that are perceived as warm or cool. Like humans, mice report forepaw skin warming with perceptual thresholds of less than 1°C and do not confuse warm with cool. We identify two populations of polymodal C-fibers that signal warm. Warm excites one population, whereas it suppresses the ongoing cool-driven firing of the other. In the absence of the thermosensitive TRPM2 or TRPV1 ion channels, warm perception was blunted, but not abolished. In addition, trpv1:trpa1:trpm3-/- triple-mutant mice that cannot sense noxious heat detected skin warming, albeit with reduced sensitivity. In contrast, loss or local pharmacological silencing of the cool-driven TRPM8 channel abolished the ability to detect warm. Our data are not reconcilable with a labeled line model for warm perception, with receptors firing only in response to warm stimuli, but instead support a conserved dual sensory model to unambiguously detect skin warming in vertebrates.status: publishe