Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features

Sickle cell anemia and β-thalassemia intermedia are very different genetically determined hemoglobinopathies predisposing to pulmonary hypertension. The etiologies responsible for the associated development of pulmonary hypertension in both diseases are multi-factorial with extensive mechanistic con...

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Autores principales:	Paul W. Buehler, Delaney Swindle, David I. Pak, Mehdi A. Fini, Kathryn Hassell, Rachelle Nuss, Rebecca B. Wilkerson, Angelo D’Alessandro, David C. Irwin
Formato:	article
Lenguaje:	EN
Publicado:	SAGE Publishing 2021
Materias:	Diseases of the circulatory (Cardiovascular) system RC666-701 Diseases of the respiratory system RC705-779
Acceso en línea:	https://doaj.org/article/a6772f4e041245f38a3c7f1237ddb78b
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spelling	oai:doaj.org-article:a6772f4e041245f38a3c7f1237ddb78b2021-11-08T23:33:19ZMurine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features2045-894010.1177/20458940211055996https://doaj.org/article/a6772f4e041245f38a3c7f1237ddb78b2021-11-01T00:00:00Zhttps://doi.org/10.1177/20458940211055996https://doaj.org/toc/2045-8940Sickle cell anemia and β-thalassemia intermedia are very different genetically determined hemoglobinopathies predisposing to pulmonary hypertension. The etiologies responsible for the associated development of pulmonary hypertension in both diseases are multi-factorial with extensive mechanistic contributors described. Both sickle cell anemia and β-thalassemia intermedia present with intra and extravascular hemolysis. And because sickle cell anemia and β-thalassemia intermedia share features of extravascular hemolysis, macrophage iron excess and anemia we sought to characterize the common features of the pulmonary hypertension phenotype, cardiac mechanics, and function as well as lung and right ventricular metabolism. Within the concept of iron, we have defined a unique pulmonary vascular iron accumulation in lungs of sickle cell anemia pulmonary hypertension patients at autopsy. This observation is unlike findings in idiopathic or other forms of pulmonary arterial hypertension. In this study, we hypothesized that a common pathophysiology would characterize the pulmonary hypertension phenotype in sickle cell anemia and β-thalassemia intermedia murine models. However, unlike sickle cell anemia, β-thalassemia is also a disease of dyserythropoiesis, with increased iron absorption and cellular iron extrusion. This process is mediated by high erythroferrone and low hepcidin levels as well as dysregulated iron transport due transferrin saturation, so there may be differences as well. Herein we describe common and divergent features of pulmonary hypertension in aged Berk-ss (sickle cell anemia) and Hbb th/3+ (intermediate β-thalassemia) mice and suggest translational utility as proof-of-concept models to study pulmonary hypertension therapeutics specific to genetic anemias.Paul W. BuehlerDelaney SwindleDavid I. PakMehdi A. FiniKathryn HassellRachelle NussRebecca B. WilkersonAngelo D’AlessandroDavid C. IrwinSAGE PublishingarticleDiseases of the circulatory (Cardiovascular) systemRC666-701Diseases of the respiratory systemRC705-779ENPulmonary Circulation, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diseases of the circulatory (Cardiovascular) system RC666-701 Diseases of the respiratory system RC705-779
spellingShingle	Diseases of the circulatory (Cardiovascular) system RC666-701 Diseases of the respiratory system RC705-779 Paul W. Buehler Delaney Swindle David I. Pak Mehdi A. Fini Kathryn Hassell Rachelle Nuss Rebecca B. Wilkerson Angelo D’Alessandro David C. Irwin Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features
description	Sickle cell anemia and β-thalassemia intermedia are very different genetically determined hemoglobinopathies predisposing to pulmonary hypertension. The etiologies responsible for the associated development of pulmonary hypertension in both diseases are multi-factorial with extensive mechanistic contributors described. Both sickle cell anemia and β-thalassemia intermedia present with intra and extravascular hemolysis. And because sickle cell anemia and β-thalassemia intermedia share features of extravascular hemolysis, macrophage iron excess and anemia we sought to characterize the common features of the pulmonary hypertension phenotype, cardiac mechanics, and function as well as lung and right ventricular metabolism. Within the concept of iron, we have defined a unique pulmonary vascular iron accumulation in lungs of sickle cell anemia pulmonary hypertension patients at autopsy. This observation is unlike findings in idiopathic or other forms of pulmonary arterial hypertension. In this study, we hypothesized that a common pathophysiology would characterize the pulmonary hypertension phenotype in sickle cell anemia and β-thalassemia intermedia murine models. However, unlike sickle cell anemia, β-thalassemia is also a disease of dyserythropoiesis, with increased iron absorption and cellular iron extrusion. This process is mediated by high erythroferrone and low hepcidin levels as well as dysregulated iron transport due transferrin saturation, so there may be differences as well. Herein we describe common and divergent features of pulmonary hypertension in aged Berk-ss (sickle cell anemia) and Hbb th/3+ (intermediate β-thalassemia) mice and suggest translational utility as proof-of-concept models to study pulmonary hypertension therapeutics specific to genetic anemias.
format	article
author	Paul W. Buehler Delaney Swindle David I. Pak Mehdi A. Fini Kathryn Hassell Rachelle Nuss Rebecca B. Wilkerson Angelo D’Alessandro David C. Irwin
author_facet	Paul W. Buehler Delaney Swindle David I. Pak Mehdi A. Fini Kathryn Hassell Rachelle Nuss Rebecca B. Wilkerson Angelo D’Alessandro David C. Irwin
author_sort	Paul W. Buehler
title	Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features
title_short	Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features
title_full	Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features
title_fullStr	Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features
title_full_unstemmed	Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features
title_sort	murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features
publisher	SAGE Publishing
publishDate	2021
url	https://doaj.org/article/a6772f4e041245f38a3c7f1237ddb78b
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Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features

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