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

Abstract

Sickle cell anemia (SCA) and β-thalassemia intermedia are very different genetically determined hemoglobinopathies predisposing to pulmonary hypertension (PH). The etiologies responsible for the associated development of PH in both diseases are multi-factorial with extensive mechanistic contributors described. Both SCA and β-thalassemia intermedia present with intra and extravascular hemolysis, and because SCA and β-thalassemia intermedia share features of extravascular hemolysis, macrophage iron excess and anemia we sought to characterize the common features of the PH 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 SCA PH 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 PH phenotype in SCA and β-thalassemia intermedia murine models, but because unlike SCA, β-thalassemia is also a disease of dyserythropoiesis, with increased iron absorption and cellular iron extrusion mediated by high erythroferrone and low hepcidin levels as well as dysregulated iron transport due transferrin saturation, there may be differences as well. Herein we describe common and divergent features of PH in aged Berk-ss (SCA) and Hbbth/3+ (intermediate β-thalassemia) mice and suggest translational utility as proof-of-concept models to study PH therapeutics specific to genetic anemias.

Innate Variability in Physiological and Omics Aspects of the Beta Thalassemia Trait-Specific Donor Variation Effects

“…RBCs from beta-thalassemic patients are characterized by decreased glutathione levels ( Kalpravidh et al, 2013 ) and, therefore, sustained oxidative stress that can be ameliorated by inhibitors of glutathione efflux transporters ( Muanprasat et al, 2013 ). In the same context, serum from beta-thalassemic subjects demonstrates down-regulated fatty acid metabolism ( Musharraf et al, 2017 ), whereas carboxylic acids and metabolites of the arginine and glutathione routes were found slightly or significantly downregulated in the lungs of murine models of beta-thalassemia ( Buehler et al, 2021 ). According to these findings, it appears that the metabolism features of β 0 RBCs are closer to the thalassemia disease profile, even though the currently studied β 0 heterozygotes were considered eligible blood donors.…”

Retention of functional mitochondria in mature red blood cells from patients with sickle cell disease

“…Since carboxylic acids, such as succinate, promote neutrophil infiltration in the lungs by activating succinate receptors, 55 the metabolic abnormality reported herein may play a role in the pathophysiology of pulmonary complications in SCD. As such, endogenous RBCs in patients with SCD may play an unexpected role in their inflammatory complications, beyond the previously described proinflammatory events resulting from increased intravascular and extravascular haemolysis 56 . Finally, increased levels of carboxylic acids and polyamines were mechanistically linked (at least in vitro ) to altered coagulation phenotypes in model pathological hypoxic settings (e.g.…”

“…As such, endogenous RBCs in patients with SCD may play an unexpected role in their inflammatory complications, beyond the previously described proinflammatory events resulting from increased intravascular and extravascular haemolysis. 56 Finally, increased levels of carboxylic acids and polyamines were mechanistically linked (at least in vitro) to altered coagulation phenotypes in model pathological hypoxic settings (e.g. haemorrhage, liver transplantation).…”

Inductively-Coupled Plasma Mass Spectrometry–Novel Insights From an Old Technology Into Stressed Red Blood Cell Physiology

“…While dysregulation of iron metabolism has been previously associated with increased propensity for lipid stress in stored RBCs or under pathological conditions (e.g., sickle cell disease or thalassemia) (Howie et al, 2019;Buehler et al, 2021), to the best of our knowledge no study has been published correlating intraand extra-cellular levels of iron to the intra-and extracellular RBC metabolome. In our study, iron levels correlated positively with markers of increased oxidant stress in aging RBCs-such as hypoxanthine (Nemkov et al, 2018b) and increased levels of poly-unsaturated fatty acids (consistent with activation of fatty acid desaturases) (Thomas et al, 2021).…”

“…Physiologically, extravascular hemolysis by means of RBC clearance prevents extracellular accumulation of damageassociated molecular pattern biomolecules, such as hemoglobin, heme, and iron in blood vessels-by diverting them to splenic catabolism (Antonelou et al, 2010). These processes are impaired in the context of stresses that accelerate aging of RBCs in vivo (e.g., sickle cell disease, thalassemia) (Buehler et al, 2021) or in vitro (blood storage) (D'Alessandro, 2021).…”