Low oxygen tension primes aortic endothelial cells to the reparative effect of tissue-protective cytokines

Erythropoietin (EPO) has both erythropoietic and tissue-protective properties. The EPO analogues carbamylated EPO (CEPO) and pyroglutamate helix B surface peptide (pHBSP) lack the erythropoietic activity of EPO but retain the tissue-protective properties that are mediated by a heterocomplex of EPO receptor (EPOR) and the β common receptor (βCR). We studied the action of EPO and its analogues in a model of wound healing where a bovine aortic endothelial cells (BAECs) monolayer was scratched and the scratch closure was assessed over 24 h under different oxygen concentrations. We related the effects of EPO and its analogues on repair to their effect on BAECs proliferation and migration (evaluated using a micro-Boyden chamber). EPO, CEPO and pHBSP enhanced scratch closure only at lower oxygen (5%), while their effect at atmospheric oxygen (21%) was not significant. The mRNA expression of EPOR was doubled in 5% compared to 21% oxygen, and this was associated with increased EPOR assessed by immunofluorescence and Western blot. By contrast βCR mRNA levels were similar in 5% and 21% oxygen. EPO and its analogues increased both BAECs proliferation and migration, suggesting that both may be involved in the reparative process. The priming effect of low oxygen tension on the action of tissue-protective cytokines may be of relevance to vascular disease, including atherogenesis and restenosis

Built environment change and change in BMI and waist circumference: Multi‐ethnic S tudy of A therosclerosis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109571/1/oby20873.pd

How much are built environments changing, and where?: Patterns of change by neighborhood sociodemographic characteristics across seven U.S. metropolitan areas

Investments in neighborhood built environments could increase physical activity and overall health. Disproportionate distribution of these changes in advantaged neighborhoods could inflate health disparities. Little information exists on where changes are occurring. This paper aims to 1) identify changes in the built environment in neighborhoods and 2) investigate associations between high levels of change and sociodemographic characteristics. Using Geographic Information Systems, neighborhood land-use, local destinations (for walking, social engagement, and physical activity), and sociodemographics were characterized in 2000 and 2010 for seven U.S. cities. Linear and change on change models estimated associations of built environment changes with baseline (2000) and change (2010–2000) in sociodemographics. Spatial patterns were assessed using Global Moran’s I to measure overall clustering of change and Local Moran’s I to identify statistically significant clusters of high increases surrounded by high increases (HH). Sociodemographic characteristics were compared between HH cluster and other tracts using Analysis of Variance (ANOVA). We observed small land-use changes but increases in the destination types. Greater increases in destinations were associated with higher percentage non-Hispanic whites, percentage households with no vehicle, and median household income. Associations were present for both baseline sociodemographics and changes over time. Greater increases in destinations were associated with lower baseline percentage over 65 but higher increases in percentage over 65 between 2000 and 2010. Global Moran’s indicated changes were spatially clustered. HH cluster tracts started with a higher percentage non-Hispanic whites and higher percentage of households without vehicles. Between 2000 and 2010, HH cluster tracts experienced increases in percent non-Hispanic white, greater increases in median household income, and larger decreases in percent of households without a vehicle. Changes in the built environment are occurring in neighborhoods across a diverse set of U.S. metropolitan areas, but are patterned such that they may lead to increased health disparities over time

Erythropoietin (EPO) increases myelin gene expression in CG4 oligodendrocyte cells through the classical EPO receptor

Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in non-hematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP)). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects

The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity

The purpose of this study is to test the role that parasympathetic postganglionic neurons could play on the adaptive electrophysiological changes produced by physical training on intrinsic myocardial automatism, conduction and refractoriness. Trained rabbits were submitted to aphysical training protocol on treadmill during 6 weeks. The electrophysiological study was performed in an isolated heart preparation. The investigated myocardial properties were: (a) sinus automatism, (b) atrioventricular and ventriculoatrial conduction, (c) atrial, conduction system and ventricular refractoriness. The parameters to study the refractoriness were obtained by means of extrastimulus test at four diVerent pacing cycle lengths (10% shorter than spontaneous sinus cycle length, 250, 200 and 150 ms) and (d) mean dominant frequency (DF) of the induced ventricular Wbrillation (VF), using a spectral method. The electrophysiological protocol was performed before and during continuous atropine administration (1 ¿M), in order to block cholinergic receptors. Cholinergic receptor blockade did not modify either the increase in sinus cycle length, atrioventricular conduction and refractoriness (left ventricular and atrioventricular conduction system functional refractory periods) or the decrease of DF of VF. These Wndings reveal that the myocardial electrophysiological modiWcations produced by physical training are not mediated by intrinsic cardiac parasympathetic activity.The authors thank Carmen Rams, Ana Diaz, Pilar Navarro and Cesar Avellaneda for their excellent technical assistance. This work has been supported by grants from the Spanish Ministry of Education and Science (DEP2007-73234-C03-01) and Generalitat Valenciana (PROMETEO 2010/093). M Zarzoso was supported by a research scholarship from Generalitat Valenciana (BFPI/2008/003).Zarzoso Muñoz, M.; Such Miquel, L.; Parra Giraldo, G.; Brines Ferrando, L.; Such, L.; Chorro, F.; Guerrero, J.... (2012). The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity. European Journal of Applied Physiology. 112(6):2185-2193. https://doi.org/10.1007/s00421-011-2189-4S218521931126Armour JA, Hopkins DA (1990a) Activity of in vivo canine ventricular neurons. Am J Physiol Heart Circ Physiol 258:H326–H336. doi: 10.1152/ajpregu.00183.2004Armour JA, Hopkins DA (1990b) Activity of canine in situ left atrial ganglion neurons. Am J Physiol Heart Circ Physiol 259:H1207–H1215Armour JA (2004) Cardiac neuronal hierarchy in health and disease. Am J Physiol Regul Integr Comp Physiol 287:R262–R271Armour JA, Murphy DA, Yuan BX, Macdonald S, Hopkins DA (1997) Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec 247:289–298Bedford TG, Tipton CM (1987) Exercise training and the arterial baroreflex. J Appl Physiol 63:1926–1932Bonaduce D, Petretta M, Cavallaro V, Apicella C, Ianniciello A, Romano M, Breglio R, Marciano F (1998) Intensive training and cardiac autonomic control in high level athletes. Med Sci Sports Exerc 30:691–696Brack KE, Coote JH, Ng GA (2011) Vagus nerve stimulation protects against ventricular fibrillation independent of muscarinic receptor activation. Cardiovasc Res 91:437–446. doi: 10.1093/cvr/cvr105Brorson L, Conradson TB, Olsson B, Varnauskas E (1976) Right atrial monophasic action potential and effective refractory periods in relation to physical training and maximal heart rate. Cardiovasc Res 10:160–168Carmeliet E, Mubagwa K (1998) Antiarrhythmic drugs and cardiac ion channels: mechanisms of action. Prog Biophys Mol Biol 70:1–72Chorro FJ, Cánoves J, Guerrero J, Mainar L, Sanchis J, Such L, López-Merino V (2000) Alteration of ventricular fibrillation by flecainide, verapamil, and sotalol: an experimental study. Circulation 101:1606–1615Di Carlo SE, Bishop VS (1990) Exercise training enhances cardiac afferent inhibition of baroreflex function. Am J Physiol 258:212–220Gagliardi M, Randall WC, Bieger D, Wurster RD, Hopkins DA, Armour JA (1988) Activity of in vivo canine cardiac plexus neurons. Am J Physiol Heart Circ Physiol 255:H789–H800Gao L, Wang W, Liu D, Zucker IH (2007) Exercise training normalizes sympathetic outflow by central antioxidant mechanisms in rabbits with pacing-induced chronic heart failure. Circulation 115:3095–3102. doi: 10.1161/CIRCULATIONAHA.106.677989Gaustad SE, Rolim N, Wisløff U (2010) A valid and reproducible protocol for testing maximal oxygen uptake in rabbits. Eur J Cardiovasc Prev Rehabil 17:83–88. doi: 10.1097/HJR.0b013e32833090c4Gómez-Cabrera MC, Borrás C, Pallardó FV, Sastre J, Ji LL, Viña J (2005) Decreasing xanthine oxidase-mediated oxidative stress prevents useful cellular adaptations to exercise in rats. J Physiol 567:113–120. doi: 10.1113/jphysiol.2004.080564Gray AL, Johnson TA, Ardell JL, Massari VJ (2004) Parasympathetic control of the heart II. A novel interganglionic intrinsic cardiac circuit mediates neural control of heart rate. J Appl Physiol 96:2273–2278. doi: 10.1152/japplphysiolHamilton KL, Powers SK, Sugiura T, Kim S, Lennon S, Tumer N, Mehta JL (2001) Short-term exercise training can improve myocardial tolerance to I/R without elevation in heat shock proteins. Am J Physiol Heart Circ Physiol 281:1346–1352Inoue H, Zipes DP (1987) Changes in atrial and ventricular refractoriness and atrioventricular nodal conduction produced by combinations of vagal and sympathetic stimulation that result in a constant spontaneous sinus cycle length. Circ Res 60:942–951Jew KN, Olsson MC, Mokelke EA, Palmer BM, Moore RL (2001) Endurance training alters outward K+ current characteristics in rat cardiocytes. J Appl Physiol 90:1327–1333Johnson TA, Gray AL, Lauenstein JM, Newton SS, Massari VJ (2004) Parasympathetic control of the heart I. An interventriculo-septal ganglion is the major source of the vagal intracardiac innervation of the ventricles. J Appl Physiol 96:2265–2272. doi: 10.1152/japplphysiol.00620.2003Katona PG, McLean M, Dighton DH, Guz A (1982) Sympathetic and parasympathetic cardiac control in athletes and nonathletes at rest. J Appl Physiol 52:1652–1657Lewis SF, Nylander E, Gad P, Areskog N (1980) Non-autonomic component in bradycardia of endurance trained men at rest and during exercise. Acta Physiol Scand 109:297–305Litovsky SH, Antzelevitch C (1990) Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol. A direct effect of acetylcholine in ventricular myocardium. Circ Res 67:615–627Löffelholz K (1981) Release of acetylcholine in the isolated heart. Am J Physiol 240(4):H431–H440Lopatin AN, Nichols CG (2001) Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol 33:625–638. doi: 10.1006/jmcc.2001.1344Mace LC, Palmer BM, Brown DA, Jew KN, Lynch JM, Glunt JM, Parsons TA, Cheung JY, Moore RL (2003) Influence of age and run training on cardiac Na+/Ca2+ exchange. J Appl Physiol 95:1994–2003. doi: 10.1152/japplphysiol.00551.2003Martins JB, Zipes DP (1980) Effects of sympathetic and vagal nerves on recovery properties of the endocardium and epicardium of the canine left ventricle. Circ Res 46:100–110Mezzani A, Giovannini T, Michelucci A, Padeletti L, Resina A, Cupelli V, Musante R (1990) Effects of training on the electrophysiologic properties of atrium and accessory pathway in athletes with Wolff–Parkinson–White syndrome. Cardiology 77:295–302Mokelke EA, Palmer BM, Cheung JY, Moore RL (1997) Endurance training does not affect intrinsic calcium current characteristics in rat myocardium. Am J Physiol Heart Circ Physiol 273:H1193–H1197Mont L, Elosua R, Brugada J (2009) Endurance sport practice as a risk factor for atrial fibrillation and atrial flutter. Europace 11:11–17. doi: 10.1093/europace/eun289Moore RL, Korzick DH (1995) Cellular adaptations of the myocardium to chronic exercise. Prog Cardiovasc Dis 37:371–396Negrao CE, Moreira ED, Santos MC, Farah VM, Krieger EM (1992) Vagal function impairment after exercise training. J Appl Physiol 72:1749–1753Ng GA, Brack KE, Coote JH (2001) Effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart—a novel model of isolated Langendorff perfused rabbit heart with intact dual autonomic innervation. Exp Physiol 86:319–329Nylander E, Sigvardsson K, Kilbom A (1982) Training-induced bradycardia and intrinsic heart rate in rats. Eur J Appl Physiol Occup Physiol 48:189–199Panfilov AV (2006) Is heart size a factor in ventricular fibrillation? Or how close are rabbit and human hearts? Heart Rhythm 3:862–864. doi: 10.1016/j.hrthm.2005.12.022Papka RE (1976) Studies of cardiac ganglia in pre- and postnatal rabbits. Cell Tissue Res 175:17–35Pardini BJ, Patel KP, Schmid PG, Lund DD (1987) Location, distribution and projections of intracardiac ganglion cells in the rat. J Auton Nerv Syst 20:91–101Scott AS, Eberhard A, Ofir D, Benchetrit G, Dinh TP, Calabrese P, Lesiuk V, Perrault H (2004) Enhanced cardiac vagal efferent activity does not explain training-induced bradycardia. Auton Neurosci 112:60–68. doi: 10.1016/j.autneu.2004.04.006Seals DR, Chase PB (1989) Influence of physical training on HR variability and baroreflex circulatory control. J Appl Physiol 66:1886–1895Shi X, Stevens GHJ, Foresman BH, Stern SA, Raven PB (1995) Autonomic nervous system control of the heart: endurance exercise training. Med Sci Sports Exerc 27:1406–1413Snyders DJ (1999) Structure and function of cardiac potassium channels. Cardiovasc Res 42:377–390Stein R, Moraes RS, Cavalcanti AV, Ferlin EL, Zimerman LI, Ribeiro JP (2000) Atrial automaticity and atrioventricular conduction in athletes: contribution of autonomic regulation. Eur J Appl Physiol 82:155–157Stein R, Moraes RS, Cavalcanti AV, Ferlin EL, Zimerman LI, Ribeiro JP (2002) Intrinsic sinus and atrioventricular node electrophysiologic adaptations in endurance athletes. J Am Coll Cardiol 39:1033–1038Stones R, Billeter R, Zhang H, Harrison S, White E (2009) The role of transient outward K+ current in electrical remodelling induced by voluntary exercise in female rat hearts. Basic Res Cardiol 104:643–652. doi: 10.1007/s00395-009-0030-6Such L, Rodríguez A, Alberola A, López L, Ruiz R, Artal L, Pons I, Pons ML, García C, Chorro FJ (2002) Intrinsic changes on automatism, conduction and refractoriness by exercise in insolated rabbit heart. J Appl Physiol 92:225–229. doi: 10.1111/j.1748-1716.2008.01851.xSuch L, Alberola AM, Such-Miquel L, López L, Trapero I, Pelechano F, Gómez-Cabrera MC, Tormos A, Millet J, Chorro FJ (2008) Effects of chronic exercise on myocardial refractoriness: a study on isolated rabbit heart. Acta Physiol 193:331–339Vigmond EJ, Tsoi V, Kuo S, Arevalo H, Kneller J, Nattel S, Trayanova N (2004) The effect of vagally induced dispersion of action potential duration on atrial arrhythmogenesis. Heart Rhythm 1:334–344. doi: 10.1016/j.hrthm.2004.03.077Zipes DP, Mihalick MJ, Robbins GT (1974) Effects of selective vagal and stellate ganglion stimulation of atrial refractoriness. Cardiovasc Res 8:647–65

Discrete land uses and transportation walking in two U.S. cities: The Multi-Ethnic Study of Atherosclerosis

This study examines associations of disaggregate land uses with self-reported walking for transportation among participants of the Multi-Ethnic Study of Atherosclerosis (MESA) in Forsyth County, NC and New York, NY. Network distance to each use (in miles), intensity (number of uses per ½-mile network buffer) of each use and diversity (number of different uses per ½-mile network buffer) of uses were calculated using Geographic Information Systems (GIS). Associations with odds of meeting recommended physical activity levels (150 min/week) were examined after controlling for individual- and census-tract-level covariates. Greater distance to and lower intensity of pedestrian-oriented uses, specifically those for social interactions, were associated with lower odds of meeting recommendations in NY. Results suggest that land uses linked to social interactions may be useful for encouraging increased transportation walking

ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response

BACKGROUND: Neuropathic pain is a difficult to treat disorder arising from central or peripheral nervous system lesions. The etiology of neuropathic pain consists of several overlapping pathways converging into an exaggerated pain state with symptoms such as allodynia and hyperalgesia. One of these pathways involves activation of spinal cord microglia and astrocytes, which drive and maintain the inflammatory response following the lesion. These cells are a potential target for drugs for neuropathic pain relief. In this current study, we investigated the dose-effect relationship of the tissue protective peptide ARA 290, derived from the tertiary structure of erythropoietin, on allodynia and concurrent spinal cord microglia and astrocytes. RESULTS: Following a spared nerve injury in rats, vehicle or ARA290 (administered in either one of 4 doses: 3, 10, 30 and 60 μg/kg) was administered on days 1, 3, 6, 8 and 10. ARA290 exerted a dose-response effect by significantly reducing mechanical allodynia up to 20 weeks when compared to vehicle. The reduction of cold allodynia was significant up to 20 weeks for the doses 3, 10, 30 and 60 μg/kg when compared to vehicle. The effect 10 and 30 μg/kg ARA290 and vehicle on the microglia response (iba-1-immunoreactivity, iba-1-IR) and astrocyte reaction (GFAP-immunoreactivity, GFAP-IR) was investigated in animals surviving 2 (group 1) or 20 (group 2) weeks following lesion or sham surgery. In group 1, significant microglia reactivity was observed in the L5 segment of the spinal cord of animals treated with vehicle when compared to sham operated, while animals treated with 10 or 30 μg/kg did not show a increase. In group 2, a more widespread and increased microglia reactivity was observed for animals treated with 0 and 10 μg/kg when compared to sham operated animals, indicated by involvement of more spinal cord segments and higher iba-1-IR. Animals treated with 30 μg/kg did not show increased microglia reactivity. No difference in astrocyte reaction was observed. CONCLUSIONS: The erythropoietin-analogue ARA290 dose-dependently reduced allodynia coupled to suppression of the spinal microglia response, suggestive of a mechanistic link between ARA290-induced suppression of central inflammation and relief of neuropathic pain symptoms.Perioperative Medicine: Efficacy, Safety and OutcomeAnesthesiolog