Gene expression, autonomic function and chronic hypoxia:lessons from the Andes.
Autonomic function is altered by altitude in sojourners and natives. We hypothesized that these physiologic responses are modulated by changes in gene expression. We compared gene product levels in 20 natives of Cerro de Pasco (CP), (4338 m), 10 of which had chronic mountain sickness (CMS) established by a CMS-scoring system, with gene products in the same men after 1 h at sea level. We further compared the results with those obtained from 10 US men residing at 1500 m. We measured gene products in white cells by reverse transcription polymerase chain reaction (RT-PCR). We focused on genes important in vascular autonomic physiology, and/or activated by hypoxia; hypoxia inducible factor 1-alpha (HIF 1-alpha), 2 splicing variants of vascular endothelial growth factor (VEGF); VEGF-121, VEGF-165, and phosphoglycerate kinase 1 (PGK 1). Normal CP natives showed high expression of all genes in CP, compared to US controls. Within 1 h of arrival at sea level, they had comparable levels to US residents. In CMS, the gene products were higher in CP. Although gene products decreased in Lima in this group, they never reached US values. VEGF 121 and 165 were correlated (P<0.001). VEGF 165 was higher in CMS in CP (P=0.006), and was positively correlated with CMS-score (R=0.86, P<0.001), and negatively correlated with arterial saturation (R=-0.79, P<0.001). Our findings underscore the changes in gene expression levels in intact humans in response to environmental stress. These changes may support the physiologic alterations induced by the ambient hypoxia at altitude and impact organism survival. They also suggest therapeutic strategies for autonomic and neurodegenerative diseases at sea level.
Appenzeller
Otto
O
New Mexico Health Enhancement and Marathon Clinics Research Foundation, Albuquerque, NM 87122-1424, USA. oarun@unm.edu
Minko
Tamara
T
Qualls
Clifford
C
Pozharov
Vitaly
V
Gamboa
Jorge
J
Gamboa
Alfredo
A
Wang
Yang
Y
D000222:Adaptation, Physiological; D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D001341:Autonomic Nervous System / Q000503:physiopathology*; D002908:Chronic Disease; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010568:Peru; D010735:Phosphoglycerate Kinase / Q000145:classification / Q000235:genetics / Q000378:metabolism; D014481:United States; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D010735:Phosphoglycerate Kinase