Objective-Abdominal aortic aneurysm (AAA) is a life-threatening disease affecting almost 10% of the population over age 65. Generation of AAAs by infusion of angiotensin (Ang) II in apolipoprotein E-knockout (ApoE Ϫ/Ϫ ) mice is an animal model which supports an imbalance of the renin-angiotensin system in the pathogenesis of AAA. The effect of statins on AngII-mediated AAA formation and the associated neovascularization is not known. Here we determined the effect of simvastatin and the ERK inhibitor, CI1040, on AngII-stimulated AAA formation. Methods and Results-ApoEϪ/Ϫ mice infused for 28 days with AngII using osmotic minipumps were treated with placebo, 10 mg/kg/d simvastatin, or 100 mg/kg/d CI1040. 95% of AngII-treated mice developed AAA with neovascularization of the lesion, increased ERK phosphorylation, MCP-1 secretion, and MMP activity. These effects were markedly reversed by simvastatin and in part by CI1040. Furthermore, simvastatin and the ERK inhibitor U0126 reversed AngII-stimulated angiogenesis and MMP secretion by human umbilical vein endothelial cells. Key Words: angiotensin II Ⅲ abdominal aortic aneurysm Ⅲ statin Ⅲ ERK inhibition Ⅲ angiogenesis A bdominal aortic aneurysm (AAA) is a potentially lifethreatening degenerative vascular disease that affects 6% to 9% of men over the age of 65 years, claiming more than 15 000 lives annually. 1 Currently, surgical repair is the only effective method of AAA treatment. 2 Studies of the pathophysiology of AAA have demonstrated that human aneurysmal tissues are characterized by (1) chronic inflammation of the aortic wall with the accumulation of macrophages and MCP-1 secretion 3 ; (2) progressive degradation of extracellular matrix including elastin and collagen 4 ; (3) increased activity of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9 5 ; (4) reendothelialization of the dilated luminal surface of the vessel wall and pronounced neovascularization of the media and adventitia. 6,7 Several animal models of AAA have been developed in the mouse, including injury of the aortic wall with calcium chloride 8 or elastase. 9 Infusion of AngII via subcutaneous osmotic minipumps in ApoE Ϫ/Ϫ mice has also been shown to result in reproducible formation of suprarenal AAAs, which exhibit many characteristics of the human disease including secretion of MCP-1, 5 macrophage infiltration, secretion of MMPs, disruption of the media, rupture of the elastic layer, and neovascularization. 10 This is consistent with the finding that AngII not only plays a role in the control of cardiovascular and renal homeostasis but also affects vascular endothelial cell function, macrophage activation, 11 and the contraction, migration, and proliferation of vascular smooth muscle cells. 12 This model supports an imbalance of the renin-angiotensin system in the pathogenesis of AAA and is thus an important model for the study of mechanisms of AAA formation. Conclusions-TheseThe mitogen-activated protein (MAP) kinase family, including ERK, c-Jun N-terminal kinase (JNK), and p38 MAPK...

Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein-coupled inward rectifying K + channel GIRK1/4 and results in an acetylcholine-sensitive K + current, I KACh . We describe a unique relationship between lipid homeostasis, the lipid-sensitive transcription factor SREBP-1, regulation of the cardiac parasympathetic response, and the development of ventricular arrhythmia. In embryonic chick atrial myocytes, lipid lowering by culture in lipoprotein-depleted serum increased SREBP-1 levels, GIRK1 expression, and I KACh activation. Regulation of the GIRK1 promoter by SREBP-1 and lipid lowering was dependent on interaction with 2 tandem sterol response elements and an upstream E-box motif. Expression of dominant negative SREBP-1 (DN-SREBP-1) reversed the effect of lipid lowering on I KACh and GIRK1. In SREBP-1 knockout mice, both the response of the heart to parasympathetic stimulation and the expression of GIRK1 were reduced compared with WT. I KACh , attenuated in atrial myocytes from SREBP-1 knockout mice, was stimulated by SREBP-1 expression. Following myocardial infarction, SREBP-1 knockout mice were twice as likely as WT mice to develop ventricular tachycardia in response to programmed ventricular stimulation. These results demonstrate a relationship between lipid metabolism and parasympathetic response that may play a role in arrhythmogenesis.

Key Words: diabetic autonomic neuropathy Ⅲ SREBP Ⅲ insulin deficiency Ⅲ GIRK channel D iabetes mellitus is associated with severe debilitating complications that include a diabetic autonomic neuropathy (DAN) characterized by impairment of vascular reflexes, occasional hypotension, and decreased sympathetic and parasympathetic responsiveness of the heart. 1 Approximately 50% of patients with diabetes for 10 years or more demonstrate an impaired response of the heart to parasympathetic stimulation. 2 The presence of DAN is a significant risk factor, as demonstrated by a 5-fold higher 5-year mortality compared with diabetics without DAN. 3 Parasympathetic regulation of the heart has both a neuronal component involving vagal stimulation of parasympathetic ganglia in the atria and atrioventricular node, followed by release of acetylcholine, and a molecular component involving an intrinsic cardiac signaling pathway that mediates the parasympathetic response to acetylcholine. The latter involves the binding of acetylcholine to M 2 muscarinic receptors on the surface of cardiomyocytes and dissociation of the heterotrimeric G protein G i2 into G␣ i2 and G␤␥ subunits. G␤␥ binds to and activates the G protein-coupled inward rectifying K ϩ channel (GIRK1) 2 /(GIRK4) 2 , the channel that is responsible for I KAch (acetylcholine-gated K ϩ current), resulting in a decrease in the rate of diastolic depolarization and a decrease in heart rate (negative chronotropic effect). 4,5

Decreased heart rate variability (HRV) is a major risk factor for sudden death and cardiovascular disease. We previously demonstrated that parasympathetic dysfunction in the heart of the Akita type 1 diabetic mouse was due to a decrease in the level of the sterol response element–binding protein (SREBP-1). Here we demonstrate that hyperactivity of glycogen synthase kinase-3β (GSK3β) in the atrium of the Akita mouse results in decreased SREBP-1, attenuation of parasympathetic modulation of heart rate, measured as a decrease in the high-frequency (HF) fraction of HRV in the presence of propranolol, and a decrease in expression of the G-protein coupled inward rectifying K+ (GIRK4) subunit of the acetylcholine (ACh)-activated inward-rectifying K+ channel (IKACh), the ion channel that mediates the heart rate response to parasympathetic stimulation. Treatment of atrial myocytes with the GSK3β inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and IKACh, whereas a dominant-active GSK3β mutant decreased SREBP-1 and GIRK4 expression. In Akita mice treated with GSK3β inhibitors Li+ and/or CHIR-99021, Li+ increased IKACh, and Li+ and CHIR-99021 both partially reversed the decrease in HF fraction while increasing GIRK4 and SREBP-1 expression. These data support the conclusion that increased GSK3β activity in the type 1 diabetic heart plays a critical role in parasympathetic dysfunction through an effect on SREBP-1, supporting GSK3β as a new therapeutic target for diabetic autonomic neuropathy.

Park HJ, Link MS, Noujaim SF, Galper JB. Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes: effect of pravastatin. Am J Physiol Heart Circ Physiol 305: H1807-H1816, 2013. First published October 25, 2013; doi:10.1152/ajpheart.00979.2012.-Although a reduction in the high-frequency (HF) component of heart rate variability (HRV) is a major complication of diabetes and a risk factor for sudden death, its relationship to ventricular tachycardia (VT) is unknown. We developed a mouse model for the study of VT and its relationship to changes in HRV in the Akita type 1 diabetic mouse. Programmed ventricular stimulation of anesthetized mice demonstrated that Akita mice were more inducible for VT compared with wild-type mice: 78.6% versus 28.6% (P ϭ 0.007). Optical mapping of perfused hearts demonstrated multifocal breakthroughs that occasionally gave rise to short-lived rotors consistent with focal initiation and maintenance of VT. Treatment of Akita mice with pravastatin, which had been previously shown clinically to decrease ventricular ectopy and to increase HRV, decreased the inducibility of VT: 36.8% compared with 75.0% with placebo treatment (P ϭ 0.022). The HF fraction of HRV was reduced in Akita mice (48.6 Ϯ 5.2% vs. 70.9 Ϯ 4.8% in wild-type mice, P ϭ 0.005) and was increased compared with placebo treatment in pravastatin-treated mice. Pretreatment of Akita mice with the muscarinic agonist carbamylcholine or the ␤-adrenergic receptor blocker propranolol decreased the inducibility of VT (P ϭ 0.001). In conclusion, the increased inducibility of focally initiated VT and reduced HF fraction in Akita mice were partially reversed by both pravastatin treatment and pharmacologic reversal of parasympathetic dysfunction. In this new animal model for the study of the pathogenesis of VT in type 1 diabetes, pravastatin may play a role in the prevention of VT by attenuating parasympathetic dysfunction. type 1 diabetes; ventricular tachycardia; statins; secondary effects of diabetes ALTHOUGH DIABETES MELLITUS is associated with an increase in cardiovascular mortality and sudden death (11), its relationship to ventricular tachycardia (VT) is not known. Risk factors for sudden death include clinical manifestations of parasympathetic dysfunction, such as a decreased high-frequency (HF), predominantly parasympathetic, component of heart rate (HR) variability (HRV) and increased dispersion of QT intervals (25,27). Furthermore, analysis of HRV in a group of patients with a history of nonsustained VT demonstrated a reduction in parasympathetic activity in conjunction with an increase in sympathetic activity before the onset of nonsustained VT, further supporting the relationship between decreased parasympathetic tone and the development of arrhythmia (21). Patients with diabetes for 10 yr have an impaired response of the heart to parasympathetic stimulation characterized by a reduction in the HF component of HRV. The increase in the incidence of sudden death in d...

Table of contentsA1 Functional advantages of cell-type heterogeneity in neural circuitsTatyana O. SharpeeA2 Mesoscopic modeling of propagating waves in visual cortexAlain DestexheA3 Dynamics and biomarkers of mental disordersMitsuo KawatoF1 Precise recruitment of spiking output at theta frequencies requires dendritic h-channels in multi-compartment models of oriens-lacunosum/moleculare hippocampal interneuronsVladislav Sekulić, Frances K. SkinnerF2 Kernel methods in reconstruction of current sources from extracellular potentials for single cells and the whole brainsDaniel K. Wójcik, Chaitanya Chintaluri, Dorottya Cserpán, Zoltán SomogyváriF3 The synchronized periods depend on intracellular transcriptional repression mechanisms in circadian clocks.Jae Kyoung Kim, Zachary P. Kilpatrick, Matthew R. Bennett, Kresimir JosićO1 Assessing irregularity and coordination of spiking-bursting rhythms in central pattern generatorsIrene Elices, David Arroyo, Rafael Levi, Francisco B. Rodriguez, Pablo VaronaO2 Regulation of top-down processing by cortically-projecting parvalbumin positive neurons in basal forebrainEunjin Hwang, Bowon Kim, Hio-Been Han, Tae Kim, James T. McKenna, Ritchie E. Brown, Robert W. McCarley, Jee Hyun ChoiO3 Modeling auditory stream segregation, build-up and bistabilityJames Rankin, Pamela Osborn Popp, John RinzelO4 Strong competition between tonotopic neural ensembles explains pitch-related dynamics of auditory cortex evoked fieldsAlejandro Tabas, André Rupp, Emili Balaguer-BallesterO5 A simple model of retinal response to multi-electrode stimulationMatias I. Maturana, David B. Grayden, Shaun L. Cloherty, Tatiana Kameneva, Michael R. Ibbotson, Hamish MeffinO6 Noise correlations in V4 area correlate with behavioral performance in visual discrimination taskVeronika Koren, Timm Lochmann, Valentin Dragoi, Klaus ObermayerO7 Input-location dependent gain modulation in cerebellar nucleus neuronsMaria Psarrou, Maria Schilstra, Neil Davey, Benjamin Torben-Nielsen, Volker SteuberO8 Analytic solution of cable energy function for cortical axons and dendritesHuiwen Ju, Jiao Yu, Michael L. Hines, Liang Chen, Yuguo YuO9 C. elegans interactome: interactive visualization of Caenorhabditis elegans worm neuronal networkJimin Kim, Will Leahy, Eli ShlizermanO10 Is the model any good? Objective criteria for computational neuroscience model selectionJustas Birgiolas, Richard C. Gerkin, Sharon M. CrookO11 Cooperation and competition of gamma oscillation mechanismsAtthaphon Viriyopase, Raoul-Martin Memmesheimer, Stan GielenO12 A discrete structure of the brain wavesYuri Dabaghian, Justin DeVito, Luca PerottiO13 Direction-specific silencing of the Drosophila gaze stabilization systemAnmo J. Kim, Lisa M. Fenk, Cheng Lyu, Gaby MaimonO14 What does the fruit fly think about values? A model of olfactory associative learningChang Zhao, Yves Widmer, Simon Sprecher,Walter SennO15 Effects of ionic diffusion on power spectra of local field potentials (LFP)Geir Halnes, Tuomo Mäki-Marttunen, Daniel Keller, Klas H. Pettersen,Ole A. Andreassen...

Background-We have previously demonstrated in an in vitro model for lipid lowering that lipoprotein depletion resulted in a marked increase in the negative chronotropic response to the acetylcholine analogue carbamylcholine. In this study we used heart rate variability analysis to determine the effect of lipid lowering by statins on the response of the heart to parasympathetic stimulation. In parallel, we examined whether changes in parasympathetic responsiveness correlated with changes in the expression of G␣ i2 , a molecular component of the parasympathetic signaling pathway in the heart. Methods and Results-Patients were randomized in a crossover study of pravastatin and simvastatin. R-R interval analysis of Holter monitor studies demonstrated that in patients treated initially with pravastatin, the peak high-frequency power fraction during sleep, which reflects parasympathetic modulation of heart rate, increased by 24.0Ϯ5.02% (SEM, nϭ13, PϽ0.001) compared with the untreated control value. Simvastatin had no significant effect. Western blot analysis of lymphocytes from patients treated with pravastatin demonstrated a 90.1Ϯ27.3% (nϭ10, Pϭ0.009) increase in G␣ i2 expression, whereas simvastatin had no effect. Relative changes in G␣ i2 correlated significantly with the changes in the fraction of high-frequency power (ϭ0.574, Pϭ0.016). Conclusions-Taken together with our in vitro data, these data are the first to suggest that cholesterol lowering by pravastatin might increase the response of the heart to parasympathetic stimulation and that changes in G␣ i2 expression might serve as a molecular marker for this effect.

BackgroundTo sustain the critical progress made, prioritization and a multidisciplinary approach to malaria research remain important to the national malaria control program in Benin. To document the structure of the malaria collaborative research in Benin, we analyze authorship of the scientific documents published on malaria from Benin.MethodsWe collected bibliographic data from the Web Of Science on malaria research in Benin from January 1996 to December 2016. From the collected data, a mulitigraph co-authorship network with authors representing vertices was generated. An edge was drawn between two authors when they co-author a paper. We computed vertex degree, betweenness, closeness, and eigenvectors among others to identify prolific authors. We further assess the weak points and how information flow in the network. Finally, we perform a hierarchical clustering analysis, and Monte-Carlo simulations.ResultsOverall, 427 publications were included in this study. The generated network contained 1792 authors and 116,388 parallel edges which converted in a weighted graph of 1792 vertices and 95,787 edges. Our results suggested that prolific authors with higher degrees tend to collaborate more. The hierarchical clustering revealed 23 clusters, seven of which form a giant component containing 94% of all the vertices in the network. This giant component has all the characteristics of a small-world network with a small shortest path distance between pairs of three, a diameter of 10 and a high clustering coefficient of 0.964. However, Monte-Carlo simulations suggested our observed network is an unusual type of small-world network. Sixteen vertices were identified as weak articulation points within the network.ConclusionThe malaria research collaboration network in Benin is a complex network that seems to display the characteristics of a small-world network. This research reveals the presence of closed research groups where collaborative research likely happens only between members. Interdisciplinary collaboration tends to occur at higher levels between prolific researchers. Continuously supporting, stabilizing the identified key brokers and most productive authors in the Malaria research collaborative network is an urgent need in Benin. It will foster the malaria research network and ensure the promotion of junior scientists in the field.