Plasticity of Gene Expression in Spaceflight and Postflight in Relation to Cardiovascular Disease: Mechanisms and Candidate Repurposed Drugs

Spaceflight poses unique challenges to human health due to exposure to increased levels of cosmic radiation, microgravity, and associated oxidative stress. These environmental factors can lead to cellular damage, inflammation, and a range of health complications, including cardiovascular problems, immune system impairment, and an increased risk of cancer. Nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor that regulates the body's defense mechanisms against oxidative stress by promoting the expression of antioxidant enzymes. Recent research has shed more light on the critical role of NRF2 in addressing space-related health challenges. In this study, we developed a computational methodology to explore the plasticity of the gene expression profile in flight and postflight conditions, highlighting the genes and corresponding mechanisms that do not return to ground levels and correlate with gene signatures associated with cardiovascular disease (CVD). RNA sequencing (RNA-seq) data from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been used to investigate the cellular effects of microgravity on cardiac function. Gene expression monotonicity studies were performed and linked to genome-wide association studies (GWAS) to highlight the monotonically expressed genes associated with CVD. The selected monotonically expressed genes were also mapped onto the NRF2 network to investigate the impact of spaceflight on human cardiomyocyte function in the context of redox signaling pathways. Based on this knowledge, we used computational drug repurposing methods to suggest a short list of repurposed drug candidates that can be further tested in astronauts for the prevention of CVD. This study provides insights into the molecular and redox signaling alterations in cardiomyocytes induced by spaceflight, laying the foundation for future research aimed at mitigating cardiovascular risks in astronauts and advancing clinical applications on Earth.