Abstract
BackgroundPulmonary hypertension and subsequent right ventricular (RV) failure are associated with high morbidity and mortality. Prognosis is determined by occurrence of RV failure. Currently, adequate treatment for RV failure is lacking. Further research into the molecular basis for the development of RV failure as well as the development of better murine models of RV failure are therefore imperative. We hypothesize that adding a low-copper diet to chronic hypoxia in mice reinforces their individual effect and that the combination of mild pulmonary vascular remodeling and capillary rarefaction, induces RV failure.MethodsSix week old mice were subjected to normoxia (N; 21% O2) or hypoxia (H; 10% O2) during a period of 8 weeks and received either a normal diet (Cu+) or a copper depleted diet (Cu-). Cardiac function was assessed by echocardiography and MRI analysis.Results and ConclusionHere, we characterized a mouse model of chronic hypoxia combined with a copper depleted diet and demonstrate that eight weeks of chronic hypoxia (10%) is sufficient to induce RV hypertrophy and subsequent RV failure. Addition of a low copper diet to hypoxia did not have any further deleterious effects on right ventricular remodeling.
Highlights
Pulmonary hypertension (PH) and subsequent right ventricular (RV) failure are associated with high morbidity and mortality
[26] Lowcopper diet interferes with HIF-1a protein stabilization, which is necessary for vascular endothelial growth factor (VEGF) expression, and subsequently affects angiogenesis. [26,28] Under hypoxic conditions, myofiber area increases two-fold, leading to a reduction in capillary density, a small increase in capillary: fiber ratio is seen as a result of modest proliferation of capillaries secondary to RV hypertrophy
Dempsey at al. showed that susceptibility to chronic hypoxia varies between species and murine susceptibility strongly depends on genetic background. [9,34] Response to hypoxia was significantly affected by the age of the animal; ‘infant’ rats of 8 days old with maturing lungs were more susceptible to a hypoxic trigger compared to older, adult animals. [8]
Summary
Pulmonary hypertension (PH) and subsequent right ventricular (RV) failure are associated with high morbidity and mortality. [6,7] Chronic hypoxia induces both vasoconstriction and remodeling of the pulmonary vascular bed resulting in increased pulmonary pressure, leading to RV failure. [8,9] This model was predominantly studied in rats, but recent studies demonstrated that mice exhibit a less severe pulmonary vascular remodeling when exposed to chronic hypoxia compared to rats. [9] In mice, chronic hypoxia induced RV hypertrophy and increased right ventricular systolic pressure (RVSP). Other rodent models of pulmonary hypertension mostly involve multiple insults, including the combination of chronic hypoxia with VEGFR inhibition (SuHx) and monocrotalin treatment with pneumonectomy, to induce pulmonary vascular remodeling and subsequent RV failure. We hypothesize that adding a low-copper diet to chronic hypoxia in mice reinforces their individual effect and that the combination of mild pulmonary vascular remodeling and capillary rarefaction, induces RV failure
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