Mutation of the von Hippel-Lindau gene alters human cardiopulmonary physiology

TY - JOUR

T1 - Mutation of the von Hippel-Lindau gene alters human cardiopulmonary physiology

AU - Smith, Thomas G

AU - Brooks, J T

AU - Balanos, G M

AU - Lappin, T R

AU - Layton, D M

AU - Leedham, D L

AU - Liu, C

AU - Maxwell, P H

AU - McMullin, M F

AU - McNamara, C J

AU - Percy, M J

AU - Pugh, C W

AU - Ratcliffe, P J

AU - Talbot, N P

AU - Treacy, M

AU - Robbins, P A

PY - 2008

Y1 - 2008

N2 - Intracellular responses to hypoxia are coordinated by the von Hippel-Lindau--hypoxia-inducible factor (VHL-HIF) transcriptional system. This study investigated the potential role of the VHL-HIF pathway in human systems-level physiology. Patients diagnosed with Chuvash polycythaemia, a rare disorder in which VHL signalling is specifically impaired, were studied during acute hypoxia and hypercapnia. Subjects breathed through a mouthpiece and ventilation was measured while pulmonary vascular tone was assessed echocardiographically. The patients were found to have elevated basal ventilation and pulmonary vascular tone, and ventilatory, pulmonary vasoconstrictive and heart rate responses to acute hypoxia were greatly increased, as were heart rate responses to hypercapnia. The patients also had abnormal pulmonary function on spirometry. This study's findings demonstrate that the VHL-HIF signalling pathway, which is so central to intracellular oxygen sensing, also regulates the organ systems upon which cellular oxygen delivery ultimately depends.

AB - Intracellular responses to hypoxia are coordinated by the von Hippel-Lindau--hypoxia-inducible factor (VHL-HIF) transcriptional system. This study investigated the potential role of the VHL-HIF pathway in human systems-level physiology. Patients diagnosed with Chuvash polycythaemia, a rare disorder in which VHL signalling is specifically impaired, were studied during acute hypoxia and hypercapnia. Subjects breathed through a mouthpiece and ventilation was measured while pulmonary vascular tone was assessed echocardiographically. The patients were found to have elevated basal ventilation and pulmonary vascular tone, and ventilatory, pulmonary vasoconstrictive and heart rate responses to acute hypoxia were greatly increased, as were heart rate responses to hypercapnia. The patients also had abnormal pulmonary function on spirometry. This study's findings demonstrate that the VHL-HIF signalling pathway, which is so central to intracellular oxygen sensing, also regulates the organ systems upon which cellular oxygen delivery ultimately depends.

KW - Basic Helix-Loop-Helix Transcription Factors/genetics

KW - Carbon Dioxide/blood

KW - Forced Expiratory Volume

KW - Heart/physiopathology

KW - Humans

KW - Hypercapnia/genetics

KW - Hypoxia/genetics

KW - Mutation

KW - Polycythemia/genetics

KW - Reference Values

KW - Respiratory Function Tests

KW - Respiratory Physiological Phenomena

KW - Signal Transduction

KW - Von Hippel-Lindau Tumor Suppressor Protein/genetics

U2 - 10.1007/978-0-387-73693-8_9

DO - 10.1007/978-0-387-73693-8_9

M3 - Article

C2 - 18085246

SN - 0065-2598

VL - 605

SP - 51

EP - 56

JO - Advances in Experimental Medicine And Biology

JF - Advances in Experimental Medicine And Biology

ER -