Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans.

Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400 mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease

High Altitude Hearts: Genetic Basis of Cardiac Responses to Long-term Hypoxia Exposures in Drosophila

Cardiomyopathy is a feature of many hypoxia-induced diseases, and affects millions of people worldwide suffering conditions including pulmonary disease, inflammation, and high altitude. Interestingly, highlanders with beneficial genetic adaptations to high altitude have remarkably low incidence of cardiomyopathies. In contrast, pathological cardiac hypertrophy is the hallmark feature of disease in other, poorly adapted highland populations. Detailed mechanisms of these cardiac responses remain largely unknown, yet examination of populations selected for survival in hypoxic environments provides a means to unravel genetic contributions to hypoxia-related disease, even for lowland populations. Drosophila, with its short lifespan and extensive genetic toolbox, is an excellent organism to investigate conserved and novel pathways underlying cardiac hypoxia responses, particularly through use of a unique population with multi-generational adaptation to hypoxia (‘hypoxia-selected’). We advance Drosophila models of cardiac hypoxia and show the fly heart responds differentially to acute, sustained, chronic and multi-generational hypoxia, and these responses are partly mediated by the HIF1α homolog, sima. We further explore hypoxia-selected fly cardiac physiology, and find effects of an acute hypoxia stress are particularly pronounced in hypoxia-selected fly hearts, even after removal of immediate environmental selection pressure. Most notably, we find persistent reduction in cardiac size in hypoxia-selected flies, but not in control flies exposed to chronic hypoxia, suggesting underlying genetic changes. We used transcriptome analyses of hypoxia-selected and chronically hypoxic fly hearts to explore contribution of calcineurin to the persistent changes observed in hypoxia-selected fly hearts. Using a heart-specific GAL4 system to modulate expression, we find knockdown of the primary calcineurin A homologues, CanA14F or Pp2B, cause cardiac restriction which phenocopies effects found in hypoxia-selected flies. We propose the calcineurin pathway as uniquely altered in the hypoxia-selected fly heart, and provide insight on mechanisms underlying cardiac adaptation to high altitude and development of cardiac disease. In summary, genes identified from hypoxia-selected populations, human or fly, can alter responses to normal cardioprotective mechanisms in the fly, as in HIFα mutants (first identified in well-adapted humans) and calcineurin-deficiency (identified in hypoxia-selected flies). We provide new insight into the physiologic mechanisms of cardiac remodeling during various hypoxia exposures, evidence for the genetic basis of cardiac adaptations, and establish markers of cardiac disease states

Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans.

Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400 mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease

Effects of altitude and ibuprofen on the hypoxic ventilatory response (HVR = ΔV˙i / ΔSa_O2).

<p>Average HVR1 (± SD), which is the initial measure of the acute HVR, is plotted for 48 hrs of treatment with placebo (Pla, gray bars) or ibuprofen (Ibu, black bars) at sea level and high altitude. There was a significant effect of altitude (p = 0.001) and altitude by drug interaction (p = 0.03). Post hoc analysis showed all of the values were significantly different from each other (p < 0.05) except the two sea level values (p = 0.22).</p

Prolonged Exposure to Microgravity Reduces Cardiac Contractility and Initiates Remodeling in Drosophila.

Understanding the effects of microgravity on human organs is crucial to exploration of low-earth orbit, the moon, and beyond. Drosophila can be sent to space in large numbers to examine the effects of microgravity on heart structure and function, which is fundamentally conserved from flies to humans. Flies reared in microgravity exhibit cardiac constriction with myofibrillar remodeling and diminished output. RNA sequencing (RNA-seq) in isolated hearts revealed reduced expression of sarcomeric/extracellular matrix (ECM) genes and dramatically increased proteasomal gene expression, consistent with the observed compromised, smaller hearts and suggesting abnormal proteostasis. This was examined further on a second flight in which we found dramatically elevated proteasome aggregates co-localizing with increased amyloid and polyQ deposits. Remarkably, in long-QT causing sei/hERG mutants, proteasomal gene expression at 1g, although less than the wild-type expression, was nevertheless increased in microgravity. Therefore, cardiac remodeling and proteostatic stress may be a fundamental response of heart muscle to microgravity