Effects of living at moderate altitude on pulmonary vascular function and exercise capacity in mice with sickle cell anaemia

Abstract

Exposure to high altitude worsens symptoms and crises in patients with sickle cell disease (SCD). However, it remains unclear whether prolonged exposure to low barometric pressures exacerbates SCD aetiologies or impairs quality of life. We tested the hypothesis that, relative to wild-type (WT) mice, Berkley sickle cell mice (BERK-SS) residing at sea level, mild (1609 m) and moderate (2438 m) altitude would have a higher rate of haemolysis, impaired cardiac function and reduced exercise tolerance, and that the level of altitude would worsen these decrements. Following 3 months of altitude exposure, right ventricular systolic pressure was measured (solid-state transducer). In addition, the adaptive balance between pulmonary vascular endothelial nitric oxide synthase and endothelin was assessed in lung tissue to determine differences in pulmonary vascular adaptation and the speed/duration relationship (critical speed) was used to evaluate treadmill exercise tolerance. At all altitudes, BERK-SS mice had a significantly lower percentage haemocrit and higher total bilirubin and free haemoglobin concentration (P < 0.05 for all). right ventricular systolic pressures in BERK-SS were higher than WT at moderate altitude and also compared to BERK-SS at sea level (P < 0.05, for both). Critical speed was significantly lower in BERK-SS at mild and moderate altitude (P < 0.05). BERK-SS demonstrated exacerbated SCD complications and reduced exercise capacity associated with an increase in altitude. These results suggest that exposure to mild and moderate altitude enhances the progression of SCD in BERK-SS mice compared to healthy WT cohorts and BERK-SS mice at sea level and provides crucial information for the clinical counselling of SCD patients.

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

“…Transgenic murine models of SCA (Berk-ss) expressing human α and β S globin 24 – 26 exhibit multi-organ pathologies that manifest spontaneously and include hemolysis resulting in severe anemia, iron accumulation (splenic, hepatic, renal, and pulmonary) and cardiopulmonary abnormalities that approximate homozygous disease in humans. 24 – 26 Deletion of both β minor and β major genes on one beta globin allele and the other normal define the β-thalassemia intermedia mice (Hbb th3/+ ) that demonstrate mild anemia, splenomegaly, and iron accumulation in all organs. 7 , 27 We report extensive iron-loaded macrophages in remodeled human SCA-PH pulmonary vascular tissue and in rodent models of SCA-PH.…”

Role of Haptoglobin as a Marker of Muscular Improvement in Patients with Multiple Sclerosis after Administration of Epigallocatechin Gallate and Increase of Beta-Hydroxybutyrate in the Blood: A Pilot Study

“…This effect can also occur at the muscle level, so that Hp binds peripherally to free Hb, carrying it to the liver and limiting its prooxidative action in the muscle [ 8 ] ( Figure 1 ). Therefore, an increase in Hp in the blood may be related to a protective activity in muscles by preventing extravasation of free Hb in the skeletal muscle tissue, thus inhibiting O2 deficiency in the skeletal muscle tissue [ 14 ]. This prevents oxidative damage and would justify its role as an antioxidant molecule, as has already been demonstrated in previous studies [ 15 , 16 ].…”

The effect of dietary nitrate supplementation on the speed-duration relationship in mice with sickle cell disease

“…In addition to the direct effects of free Hb on skeletal muscle vascular and metabolic function, it has recently been demonstrated that the Berkeley mouse model of SCD (BERK) exhibits impaired exercise tolerance due, at least in part, to right heart insufficiency and pulmonary hypertension linked to reduced NO bioavailability (22). A major strength of this previ-Correspondence: S. K. Ferguson (Scott.Ferguson@Hawaii.edu).…”