Simulated Microgravity Alters Gene Regulation Linked to Immunity and Cardiovascular Disease

Author:

Tahimic Candice G. T.12,Steczina Sonette23ORCID,Sebastian Aimy4ORCID,Hum Nicholas R.4ORCID,Abegaz Metadel23,Terada Masahiro25,Cimini Maria6,Goukassian David A.7,Schreurs Ann-Sofie25,Hoban-Higgins Tana M.8,Fuller Charles A.8,Loots Gabriela G.49ORCID,Globus Ruth K.2,Shirazi-Fard Yasaman2

Affiliation:

1. Department of Biology, University of North Florida, Jacksonville, FL 32224, USA

2. Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA

3. Blue Marble Space Institute of Science, Seattle, WA 98104, USA

4. Lawrence Livermore National Laboratory, Livermore, CA 94550, USA

5. Universities Space Research Association, Washington, DC 20024, USA

6. Temple University School of Medicine, Philadelphia, PA 19140, USA

7. Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

8. Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, USA

9. Department of Orthopedic Surgery, University of California Davis Health, Sacramento, CA 95817, USA

Abstract

Microgravity exposure induces a cephalad fluid shift and an overall reduction in physical activity levels which can lead to cardiovascular deconditioning in the absence of countermeasures. Future spaceflight missions will expose crew to extended periods of microgravity among other stressors, the effects of which on cardiovascular health are not fully known. In this study, we determined cardiac responses to extended microgravity exposure using the rat hindlimb unloading (HU) model. We hypothesized that exposure to prolonged simulated microgravity and subsequent recovery would lead to increased oxidative damage and altered expression of genes involved in the oxidative response. To test this hypothesis, we examined hearts of male (three and nine months of age) and female (3 months of age) Long–Evans rats that underwent HU for various durations up to 90 days and reambulated up to 90 days post-HU. Results indicate sex-dependent changes in oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) and antioxidant gene expression in left ventricular tissue. Three-month-old females displayed elevated 8-OHdG levels after 14 days of HU while age-matched males did not. In nine-month-old males, there were no differences in 8-OHdG levels between HU and normally loaded control males at any of the timepoints tested following HU. RNAseq analysis of left ventricular tissue from nine-month-old males after 14 days of HU revealed upregulation of pathways involved in pro-inflammatory signaling, immune cell activation and differential expression of genes associated with cardiovascular disease progression. Taken together, these findings provide a rationale for targeting antioxidant and immune pathways and that sex differences should be taken into account in the development of countermeasures to maintain cardiovascular health in space.

Funder

NASA Human Research Program Human Health Countermeasures

NASA Space Biology Postdoctoral Program

U.S. Department of Energy by Lawrence Livermore National Laboratory

Publisher

MDPI AG

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