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Paracrine erythropoietin (EPO) signaling and anti‐apoptosis in the lungs of guinea pigs exposed to high altitude (HA)
Author(s) -
Hsia Connie C.W.,
Zhang Qiuyang Daniel,
Foster David J.,
Ravikumar Priya,
Powell Frank L.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.861.10
Subject(s) - autocrine signalling , paracrine signalling , erythropoietin receptor , endocrinology , medicine , biology , erythropoietin , receptor , signal transduction , apoptosis , microbiology and biotechnology , biochemistry
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.