Early Transcriptomic Signatures of Reductive Stress Cardiomyopathy Reveal Insufficient HIF-1α Signaling

Abstract Chronic activation of Nrf2-regulated antioxidant pathways can lead to a pathological condition known as reductive stress (RS). While transient Nrf2 activation confers protection against oxidative stress, its sustained stimulation may provoke maladaptive responses in high-energy-demanding organs such as the heart. In this study, we employed a cardiac-specific constitutively active Nrf2 transgenic (CaNrf2-TG) mouse model to characterize early transcriptomic alterations associated with the transition from compensated cardiac function to pathological remodeling. Myocardial RNA sequencing at 12 weeks of age, a critical window preceding overt cardiac dysfunction, revealed widespread dysregulation of antioxidants, immune, metabolic, proteostasis(definition), and stress-response pathways. Notably, genes related to HIF-1 signaling, PI3K-Akt, MAPK, and hypertrophic cardiomyopathy were significantly altered. Functional enrichment analysis highlighted upregulation of detoxification enzymes and stress response regulators, alongside downregulation of ER chaperones, calcium-handling proteins, and MHC-II immune mediators. Furthermore, perturbations in metabolic flexibility and sarcomeric gene expression suggest early disruption of structural and energy-regulating networks. These findings uncover early molecular signatures of Nrf2-driven RS cardiomyopathy and may aid in identifying potential therapeutic targets for mitigating disease progression.