Intermedin modulates hypoxic pulmonary vascular remodeling by inhibiting pulmonary artery smooth muscle cell proliferation |
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| Institution: | 1. Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China;2. The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA;1. Unidad de Biotecnología del Centro de Investigación Científica de Yucatán A.C., Calle 43, No. 130, Col. Chuburná de Hidalgo, CP 97200 Mérida, Yucatán, Mexico;2. División de Biología Celular y Molecular, Centro de Investigación Biomédica del Noreste, IMSS, San Luis Potosí y 2 de Abril, Col. Independencia, CP 65720 Monterrey, Nuevo León, Mexico;3. Departamento de Ciencias Básicas, División de Ciencia de la Salud, Universidad de Monterrey, Ave. Ignacio Morones Prieto 4500 Pte., CP 66238 San Pedro Garza García, Nuevo León, Mexico;4. Unidad de Recursos Naturales del Centro de Investigación Científica de Yucatán A.C., Calle 43, No. 130, Col. Chuburná de Hidalgo, CP 97200 Mérida, Yucatán, Mexico;1. Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, The University of Nottingham, Nottingham, UK;2. Division of Therapeutics and Molecular Medicine, University of Nottingham, UK;3. Procter & Gamble, Whitehall Lane, Egham, Surrey, UK;4. Procter & Gamble, Mason, OH, USA;1. Division of Immunology, Allergy and Infectious Diseases, Experimental Allergy, Department of Dermatology, Medical University of Vienna, Vienna, Austria;2. Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria;3. Department of Pulmonary Disease Research, Boehringer-Ingelheim Pharma, Biberach, Germany;1. Institut de Physiologie et Biologie Cellulaires CNRS FRE3511, Université de Poitiers, Poitiers, France;2. Service de chirurgie cardiothoracique, CHU La Milétrie, Poitiers, France;1. National Reference Center for Hantavirus, Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium;2. Institute of Tropical Medicine Antwerp, Kronenburgstraat 43/3, 2000 Antwerp, Belgium |
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| Abstract: | BackgroundHypoxic pulmonary arterial hypertension (PAH) is a disabling disease with limited treatment options. Hypoxic pulmonary vascular remodeling is a major cause of hypoxic PAH. Pharmacological agents that can inhibit the remodeling process may have great therapeutic value.ObjectiveTo examine the effect of intermedin (IMD), a new calcitonin gene-related peptide family of peptide, on hypoxic pulmonary vascular remodeling.MethodsRats were exposed to normoxia or hypoxia (∼10% O2), or exposed to hypoxia and treated with IMD, administered by an implanted mini-osmotic pump (6.5 μg/rat/day), for 4 weeks. The effects of IMD infusion on the development of hypoxic PAH and right ventricle (RV) hypertrophy, on pulmonary vascular remodeling, on pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, and on the activations of l-arginine nitric oxide (NO) pathway and endoplasmic reticulum stress apoptotic pathway were examined.ResultsRats exposed to hypoxia developed PAH and RV hypertrophy. IMD treatment alleviated PAH and prevented RV hypertrophy. IMD inhibited hypoxic pulmonary vascular remodeling as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-exposed rats. IMD treatment inhibited PASMC proliferation and promoted PASMC apoptosis. IMD treatment increased tissue level of constitutive NO synthase activity and tissue NO content in lungs, and enhanced l-arginine uptake into pulmonary vascular tissues. IMD treatment increased cellular levels of glucose-regulated protein (GRP) 78 and GRP94, two major markers of endoplasmic reticulum (ER) stress, and increased caspase-12 expression, the ER stress-specific caspase, in lungs and cultured PASMCs.ConclusionsThese results demonstrate that IMD treatment attenuates hypoxic pulmonary vascular remodeling, and thereby hypoxic PAH mainly by inhibiting PASMC proliferation. Promotion of PASMC apoptosis may also contribute to the inhibitory effect of IMD. Activations l-arginine–NO pathway and of ER stress-specific apoptosis pathway could be the mechanisms mediating the anti-proliferative and pro-apoptotic effects of IMD. |
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| Keywords: | Hypoxia Pulmonary arterial hypertension Intermedin Proliferation Endoplasmic reticulum stress |
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