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      Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K Ca2.3 and K Ca3.1 Channels

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          Abstract

          Objective

          In vascular biology, endothelial K Ca2.3 and K Ca3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of K Ca2.3 and K Ca3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of K Ca2.3 and K Ca3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension.

          Approach and Result

          Male wild type and K Ca3.1 −/−/K Ca2.3 T/T(+DOX) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The K Ca3.1 −/−/K Ca2.3 T/T(+DOX) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the K Ca2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the K Ca2.3 and K Ca3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of K Ca2.3 and K Ca3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype.

          Conclusion

          Despite the deficits of the K Ca2.3 and K Ca3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of K Ca2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of K Ca2.3/K Ca3.1 activators for the treatment of pulmonary hypertension.

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          Most cited references51

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          An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry.

          The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) was established to characterize the clinical course, treatment, and predictors of outcomes in patients with pulmonary arterial hypertension (PAH) in the United States. To date, estimated survival based on time of patient enrollment has been established and reported. To determine whether the survival of patients with PAH has improved over recent decades, we assessed survival from time of diagnosis for the REVEAL Registry cohort and compared these results to the estimated survival using the National Institutes of Health (NIH) prognostic equation. Newly or previously diagnosed patients (aged ≥ 3 months at diagnosis) with PAH enrolled from March 2006 to December 2009 at 55 US centers were included in the current analysis. A total of 2,635 patients qualified for this analysis. One-, 3-, 5-, and 7-year survival rates from time of diagnostic right-sided heart catheterization were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91% ± 2%, 74% ± 2%, 65% ± 3%, and 59% ± 3% compared with estimated survival rates of 68%, 47%, 36%, and 32%, respectively, using the NIH equation. Comprehensive analysis of survival from time of diagnosis in a large cohort of patients with PAH suggests considerable improvements in survival in the past 2 decades since the establishment of the NIH registry, the effects of which most likely reflect a combination of changes in treatments, improved patient support strategies, and possibly a PAH population at variance with other cohorts
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            Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms.

            Chronic hypoxic exposure induces changes in the structure of pulmonary arteries, as well as in the biochemical and functional phenotypes of each of the vascular cell types, from the hilum of the lung to the most peripheral vessels in the alveolar wall. The magnitude and the specific profile of the changes depend on the species, sex, and the developmental stage at which the exposure to hypoxia occurred. Further, hypoxia-induced changes are site specific, such that the remodeling process in the large vessels differs from that in the smallest vessels. The cellular and molecular mechanisms vary and depend on the cellular composition of vessels at particular sites along the longitudinal axis of the pulmonary vasculature, as well as on local environmental factors. Each of the resident vascular cell types (ie, endothelial, smooth muscle, adventitial fibroblast) undergo site- and time-dependent alterations in proliferation, matrix protein production, expression of growth factors, cytokines, and receptors, and each resident cell type plays a specific role in the overall remodeling response. In addition, hypoxic exposure induces an inflammatory response within the vessel wall, and the recruited circulating progenitor cells contribute significantly to the structural remodeling and persistent vasoconstriction of the pulmonary circulation. The possibility exists that the lung or lung vessels also contain resident progenitor cells that participate in the remodeling process. Thus the hypoxia-induced remodeling of the pulmonary circulation is a highly complex process where numerous interactive events must be taken into account as we search for newer, more effective therapeutic interventions. This review provides perspectives on each of the aforementioned areas.
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              K+ is an endothelium-derived hyperpolarizing factor in rat arteries.

              In arteries, muscarinic agonists such as acetylcholine release an unidentified, endothelium-derived hyperpolarizing factor (EDHF) which is neither prostacyclin nor nitric oxide. Here we show that EDHF-induced hyperpolarization of smooth muscle and relaxation of small resistance arteries are inhibited by ouabain plus Ba2+; ouabain is a blocker of Na+/K+ ATPase and Ba2+ blocks inwardly rectifying K+ channels. Small increases in the amount of extracellular K+ mimic these effects of EDHF in a ouabain- and Ba2+-sensitive, but endothelium-independent, manner. Acetylcholine hyperpolarizes endothelial cells and increases the K+ concentration in the myoendothelial space; these effects are abolished by charbdotoxin plus apamin. Hyperpolarization of smooth muscle by EDHF is also abolished by this toxin combination, but these toxins do not affect the hyperpolarizaiton of smooth muscle by added K+. These data show that EDHF is K+ that effluxes through charybdotoxin- and apamin-sensitive K+ channels on endothelial cells. The resulting increase in myoendothelial K+ concentration hyperpolarizes and relaxes adjacent smooth-muscle cells by activating Ba2+-sensitive K+ channels and Na+/K+ ATPase. These results show that fluctuations in K+ levels originating within the blood vessel itself are important in regulating mammalian blood pressure and flow.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                23 May 2014
                : 9
                : 5
                : e97687
                Affiliations
                [1 ]Department of Biomedicine, Aarhus University, Aarhus, Denmark
                [2 ]Institute for Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
                [3 ]Aragon Institute of Health Sciences I+CS and ARAID, Zaragoza, Spain
                Indiana University, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CWF ERH RK US. Performed the experiments: CWF LMS VS GN SM. Analyzed the data: CWF LMS VS GN ERH SM RK US. Contributed reagents/materials/analysis tools: RK US. Wrote the paper: CWF RK US. Obtained permission for the animal experiments: US.

                Article
                PONE-D-13-46875
                10.1371/journal.pone.0097687
                4032241
                24858807
                f85bbbcd-f2da-4b54-ae33-51cceb7a5caf
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 November 2013
                : 22 April 2014
                Page count
                Pages: 11
                Funding
                NovoNordisk Foundation supported Ulf Simonsen and Ralf Köhler. Ulf Simonsen is supported by the Danish Heart Foundation and he is member of LiPhos (Living Photonics: Monitoring light propagation through cells), which is funded by the EC Seventh Framework programme. Ralf Köhler is supported by a grant of the Deutsche Forschungsgemeinschaft (KO1899/11-1) and the Fondo de Investigación Sanitaria (Red HERACLES RD12/0042/0014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Agriculture
                Agricultural Biotechnology
                Genetically Modified Organisms
                Transgenic Animals
                Anatomy
                Cardiovascular Anatomy
                Biotechnology
                Genetic Engineering
                Cell Biology
                Molecular Cell Biology
                Genetics
                Gene Expression
                Medicine and Health Sciences
                Cardiology
                Cardiovascular Pharmacology
                Hematology
                Hemodynamics
                Pulmonology
                Pulmonary Vascular Diseases
                Vascular Medicine
                Blood Pressure
                Hypertension
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Mouse Models

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                Uncategorized

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