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