Dilated Hearts at High Altitude: Words From On High

Lankford, Harvey V.; Swenson, Erik R.

doi:10.1089/ham.2014.1047

Cited by 11 publications

(11 citation statements)

References 25 publications

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“…5,6,13,43 We suggest that calcineurins are involved in regulating this process, based on our findings and their known roles promoting the metabolic shift toward glycolysis during pathological car-diomyopathies. 23,32 Moreover, active calcineurin stabilizes the HIF and, thus, favors a shift toward glycolysis, 1,23 a shift which is also observed in whole HS flies.…”

Section: Discussionsupporting

confidence: 55%

“…6,7 However, other high-altitude populations exhibit signs of cardiac disease, including cardiomyopathies and pathological hypertrophy because of multigenerational exposure to hypoxia. 5,48 Recent evidence from high-altitude human and model organisms, including flies exposed to hypoxia, indicates shared genetic and physiological adaptations based on selection for long-term hypoxia survival. 49 Intriguingly, one of the few genomic regions found to be under positive selection in both HS flies and in multiple, well-adapted human populations contains SPRY , the fly homolog s prouty , a proposed negative regulator of epidermal growth factor that impacts calcineurin function, although no mechanism had been suggested for this gene in long-term hypoxia adaptation.…”

Section: Discussionmentioning

confidence: 99%

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Reduced Cardiac Calcineurin Expression Mimics Long-Term Hypoxia-Induced Heart Defects in Drosophila

Zarndt

Walls

Ocorr

et al. 2017

Circ Cardiovasc Genet

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Background Hypoxia is often associated with cardiopulmonary diseases, which represent some of the leading causes of mortality worldwide. Long-term hypoxia exposures, whether from disease or environmental condition, can cause cardiomyopathy and lead to heart failure. Indeed, hypoxia-induced heart failure is a hallmark feature of chronic mountain sickness in maladapted populations living at high altitude. In a previously established Drosophila heart model for long-term hypoxia exposure, we found that hypoxia caused heart dysfunction. Calcineurin is known to be critical in cardiac hypertrophy under normoxia, but its role in the heart under hypoxia is poorly understood. Methods and Results In the present study, we explore the function of calcineurin, a gene candidate we found downregulated in the Drosophila heart after lifetime and multigenerational hypoxia exposure. We examined the roles of 2 homologs of Calcineurin A, CanA14F, and Pp2B in the Drosophila cardiac response to long-term hypoxia. We found that knockdown of these calcineurin catalytic subunits caused cardiac restriction under normoxia that are further aggravated under hypoxia. Conversely, cardiac overexpression of Pp2B under hypoxia was lethal, suggesting that a hypertrophic signal in the presence of insufficient oxygen supply is deleterious. Conclusions Our results suggest a key role for calcineurin in cardiac remodeling during long-term hypoxia with implications for diseases of chronic hypoxia, and it likely contributes to mechanisms underlying these disease states.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Reduced Cardiac Calcineurin Expression Mimics Long-Term Hypoxia-Induced Heart Defects in Drosophila

Zarndt

Walls

Ocorr

et al. 2017

Circ Cardiovasc Genet

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“…Tibetan pigs, which have a long history of living at high altitude and have experienced strong selection, have a well-developed heart, and are well adapted to low oxygen conditions [22]. Immigrant mammals that migrate to high altitudes are exposed to chronic hypoxia, which would result in cardiac hypertrophy and eventual heart failure [39, 40]. We believe that the 384 DMGs identified by comparing TH vs. YH, were of the most interest as potential candidate genes for high-altitude adaptation in Tibetan pigs.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation profiles in Tibetan and Yorkshire pigs under high-altitude hypoxia

Zhang

Ban

Gou

et al. 2019

J Animal Sci Biotechnol

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Background Tibetan pigs, which inhabit the Tibetan Plateau, exhibit distinct phenotypic and physiological characteristics from those of lowland pigs and have adapted well to the extreme conditions at high altitude. However, the genetic and epigenetic mechanisms of hypoxic adaptation in animals remain unclear. Methods Whole-genome DNA methylation data were generated for heart tissues of Tibetan pigs grown in the highland (TH, n = 4) and lowland (TL, n = 4), as well as Yorkshire pigs grown in the highland (YH, n = 4) and lowland (YL, n = 4), using methylated DNA immunoprecipitation sequencing. Results We obtained 480 million reads and detected 280679, 287224, 259066, and 332078 methylation enrichment peaks in TH, YH, TL, and YL, respectively. Pairwise TH vs. YH, TL vs. YL, TH vs. TL, and YH vs. YL comparisons revealed 6829, 11997, 2828, and 1286 differentially methylated regions (DMRs), respectively. These DMRs contained 384, 619, 192, and 92 differentially methylated genes (DMGs), respectively. DMGs that were enriched in the hypoxia-inducible factor 1 signaling pathway and pathways involved in cancer and hypoxia-related processes were considered to be important candidate genes for high-altitude adaptation in Tibetan pigs. Conclusions This study elucidates the molecular and epigenetic mechanisms involved in hypoxic adaptation in pigs and may help further understand human hypoxia-related diseases. Electronic supplementary material The online version of this article (10.1186/s40104-019-0316-y) contains supplementary material, which is available to authorized users.

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“…Reduction in LV mass correlated with loss of skeletal muscle mass, both being reversed to baseline values after 6 weeks at sea level. Elevated levels of IL‐18 might be studied further as a common contributing mechanism for cardiac remodelling and loss of muscle mass at extreme altitude (Lankford & Swenson, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Extreme altitude induces divergent mass reduction of right and left ventricle in mountain climbers

Udjus

Sjaastad

Hjørnholm

et al. 2022

Physiological Reports

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Mountain climbing at high altitude implies exposure to low levels of oxygen, low temperature, wind, physical and psychological stress, and nutritional insufficiencies. We examined whether right ventricular (RV) and left ventricular (LV) myocardial masses were reversibly altered by exposure to extreme altitude. Magnetic resonance imaging and echocardiography of the heart, dual x‐ray absorptiometry scan of body composition, and blood samples were obtained from ten mountain climbers before departure to Mount Everest or Dhaulagiri (baseline), 13.5 ± 1.5 days after peaking the mountain (post‐hypoxia), and six weeks and six months after expeditions exceeding 8000 meters above sea level. RV mass was unaltered after extreme altitude, in contrast to a reduction in LV mass by 11.8 ± 3.4 g post‐hypoxia ( p = 0.001). The reduction in LV mass correlated with a reduction in skeletal muscle mass. After six weeks, LV myocardial mass was restored to baseline values. Extreme altitude induced a reduction in LV end‐diastolic volume (20.8 ± 7.7 ml, p = 0.011) and reduced E’, indicating diastolic dysfunction, which were restored after six weeks follow‐up. Elevated circulating interleukin‐18 after extreme altitude compared to follow‐up levels, might have contributed to reduced muscle mass and diastolic dysfunction. In conclusion, the mass of the RV, possibly exposed to elevated afterload, was not changed after extreme altitude, whereas LV mass was reduced. The reduction in LV mass correlated with reduced skeletal muscle mass, indicating a common denominator, and elevated circulating interleukin‐18 might be a mechanism for reduced muscle mass after extreme altitude.

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Dilated Hearts at High Altitude: Words From On High

Cited by 11 publications

References 25 publications

Reduced Cardiac Calcineurin Expression Mimics Long-Term Hypoxia-Induced Heart Defects in Drosophila

Reduced Cardiac Calcineurin Expression Mimics Long-Term Hypoxia-Induced Heart Defects in Drosophila

Genome-wide DNA methylation profiles in Tibetan and Yorkshire pigs under high-altitude hypoxia

Extreme altitude induces divergent mass reduction of right and left ventricle in mountain climbers

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