Please cite this article in press as: Llanos, A.J., et al., The heme oxygenase–carbon monoxide system in the regulation of cardiorespiratory function at high altitude. Respir. Physiol. Neurobiol. (2012), http://dx.doi.org/10.1016/j.resp.2012.05.003 ARTICLE IN PRESS G Model RESPNB-1817; No. of Pages 6 Respiratory Physiology & Neurobiology xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Respiratory Physiology & Neurobiology j our nal ho me p age: www.elsevier.com/locate/resphysiol Review The heme oxygenase–carbon monoxide system in the regulation of cardiorespiratory function at high altitude  Aníbal J. Llanos a,b,∗ , Germán Ebensperger a , Emilio A. Herrera a,b , Roberto V. Reyes a , Gertrudis Cabello c , Marcela Díaz a , Dino A. Giussani d , Julian T. Parer e a Unidad de Fisiología y Fisiopatología Perinatal (UFFP), Programa de Fisiopatología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile b International Center for Andean Studies (INCAS), Universidad de Chile, Santiago-Arica-Putre, Chile c Departamento de Biología, Facultad de Ciencias, Universidad de Tarapacá, Arica, Chile d Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK e Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, USA a r t i c l e i n f o Article history: Accepted 2 May 2012 Keywords: Pulmonary vasodilatation Vascular remodeling hypoxia CORM Carbon monoxide Heme oxygenase a b s t r a c t Pulmonary arterial hypertension is one of the most serious pathologies that can affect the 140 million people living at altitudes over 2500 m. The primary emphasis of this review is pulmonary artery hyper- tension in mammals (sheep and llamas) at high altitude, with specific focus on the heme oxygenase and carbon monoxide (HO–CO) system. We highlight the fact that the neonatal llama has neither pulmonary artery hypertension nor pulmonary vascular remodeling in the Andean altiplano. These neonates have an enhanced HO–CO system function, increasing the HO-1 protein expression and CO production by the pulmonary vessels, when compared to llamas raised at low altitude, or neonatal sheep raised at high altitude. The neonatal sheep has high altitude pulmonary artery hypertension in spite of enhancement of the NO system, with high eNOS protein expression and NO production by the lung. The gasotransmitters NO and CO are important in the regulation of the pulmonary vascular function at high altitudes in both high altitude acclimatized species, such as the sheep, and high altitude adapted species, such as the llama. © 2012 Elsevier B.V. All rights reserved. “. . ..carbon monoxide renders the blood crimson throughout the whole of the circulatory system.” Claude Bernard, 1846 Abbreviations: BKCa, big conductance calcium dependent potassium channel; cGMP, cyclic guanosine monophosphate; CO, carbon monoxide; COHb, carboxyhe- moglobin; CORMs, carbon monoxide releasing molecules; eNOS, endothelial nitric oxide synthase; HHH, neonates whose conception, gestation, delivery and neona- tal period took place at high altitude; HO, heme oxygenase; LLL, neonates whose conception, gestation, delivery and neonatal period took place at low altitude; LHL, neonatal lambs in which the conception and 30% gestation took place at low altitude, then 70% gestation and delivery occurred at high altitude and finally the neona- tal period ensued at low altitude; l-NAME, l-arginine methyl ester; mPAP, mean pulmonary arterial pressure; NA, not available; NO, nitric oxide; NOS, nitric oxide synthase; PDE-5, phosphodiesterase 5; PO2, arterial oxygen partial pressure; PVR, pulmonary vascular resistance; sGC, soluble isoform of guanylyl cyclase.  This paper is part of a special issue entitled “Gasotransmitters and Respiration: Consequences in Health and Disease”, guest-edited by Prem Kumar and Chris S. Peers. ∗ Corresponding author at: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 16038, Santiago 9, Chile. Tel.: +56 2 341 9147; fax: +56 2 274 1628. E-mail address: allanos@med.uchile.cl (A.J. Llanos). Fair is foul and foul is fair Act I. Scene II Macbeth, W. Shakespeare 1. Introduction Mothers, fetuses and neonates can experience acute and/or chronic hypoxia anywhere on the planet. However the possibility of episodes of acute or chronic hypoxia superimposed on the basal chronic hypoxia of life at high altitude is a substantial added risk. More than 140 million people live at altitudes greater than 2500 m (Moore et al., 2004) comprising the largest single human group at risk for perinatal complications due to low PO 2. This is a poorly rec- ognized world-wide public health problem, and those affected are mainly located in developing countries. One of the more serious pathologies associated with high altitude in various species is pulmonary hypertension, initially pro- duced by pulmonary vasoconstriction and later exacerbated by vascular remodeling (Canepa et al., 1956; Gamboa and Marticorena, 1971; Penaloza and Arias-Stella, 2007). Under certain acute condi- tions increases in pulmonary arterial vascular resistance may be 1569-9048/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resp.2012.05.003