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Anti-ischemic therapy remains a challenge due to the complexity of hypoxia response pathways.Hypoxia-inducible factor (HIF)-1 is a heterodimer transcription factor consisting of 2 subunits,HIF-1α and HIF-1β.Hypoxia-dependent activation of HIF-1α regulates cellular O2 homeostasis.Raynaud syndrome (RS),as a comorbidity of the autoimmune disease systemic sclerosis (SS),is characterized by vasospasms that limit blood flow to the limbs,resulting in hypoxia.A single-center randomized study was conducted to compare prostaglandin E1 (PgE1) therapy with a treatment combining PgE1 and an endothelin-1 blocker,bosentan.A total of 30 patients suffering from SS with RS were enrolled.We examined the regulation of HIF-1α,its target heme oxygenase-1 (HMOX-1),and the serum levels of the HIF-1α protein in a subset of patients as well as in ten healthy individuals.The expression of HIF-1α and HMOX-1 in monocytes was measured using absolute plasmid-based quantitative real-time PCR,whereas serum HIF-1α levels were measured with ELISA.Samples were taken at the time of randomization and after 24 weeks.We found that HIF-1α and HMOX-1 mRNA expression in monocytes and serum HIF-1α protein levels were significantly higher in the SS/RS patients compared to the healthy control group.Single-drug therapy significantly increased HIF-1α and HMOX-1 mRNA expression in monocytes and serum HIF-1α protein levels in the SS/RS patients compared to those at the time of randomization,whereas combining PgE1 with an endothelin-1 blocker prevented the further increases in HIF-1cα and HMOX-1 expression.We propose HIF-1α and HMOX-1 as novel markers for anti-ischemic therapy in RS.