Paracrine erythropoietin (EPO) signaling and anti‐apoptosis in the lungs of guinea pigs exposed to high altitude (HA)

Abstract

HA residence stimulates erythropoiesis as well as lung growth and remodeling in young animals, suggesting parallel upregulation of endocrine and paracrine/autocrine EPO signaling. To examine this possibility, we exposed weanling male guinea pigs to 3,800 m HA for 3 d, 7 d or 1 mo compared to matched controls at sea level (SL) (n = 5–8 each), and measured mRNA and/or protein expression of hypoxia‐inducible factors (HIF‐1alpha and ‐2alpha), EPO and its receptor (EPOR), Jak2, VEGF and its receptors (−R1, −R2), endothelin‐1 (ET‐1), proliferation marker (PCNA), and an apoptotic suppressor (Bcl‐2) and a promoter (BAD). Compared to SL, HA‐exposed lungs showed 100% and 50% higher HIF‐1alpha mRNA at 3 and 7 d and 55% lower HIF‐2alpha mRNA at 3 d, although HIF‐2alpha protein was 120% higher. Lung EPO mRNA and cytoplasmic EPOR protein increased 150% and 25% at 3 d without significant changes in membrane EPOR or Jak2. Plasma and urine EPO protein increased 56% and 160% at 3 d. Lung VEGF‐R2 protein increased 72% at 3 d while VEGF increased 27% at 7 d. ET‐1 mRNA increased 3‐fold at 3 and 7 d. BAD was 50% lower and Bcl‐2 100% higher at 3 d. PCNA was unaltered. All changes resolved by 1 mo. Thus, short‐term HA exposure stimulates both endocrine and paracrine/autocrine EPO signaling. Enhanced EPO signaling in the lung occurs primarily at the ligand but not the receptor level and is associated with anti‐apoptosis. Support: NIH R01 HL045716.