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deficiency impairs pulmonary
arterial myocyte electrophysiological responses to hypoxia
Division of Pulmonary and Critical Care Medicine and Institute of Genetic Medicine, Departments of Medicine and Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21224
Chronic hypoxia
depolarizes and reduces K+ current in pulmonary arterial
smooth muscle cells (PASMCs). Our laboratory previously demonstrated
that hypoxia-inducible factor-1 (HIF-1) contributed to the development
of hypoxic pulmonary hypertension. In this study, electrophysiological
parameters were measured in PASMCs isolated from intrapulmonary
arteries of mice with one null allele at the Hif1a locus
encoding HIF-1
[Hif1a(+/
)] and from their wild-type
[Hif1a(+/+)] littermates after 3 wk in air or 10%
O2. Hematocrit and right ventricular wall and left
ventricle plus septum weights were measured. Capacitance,
K+ current, and membrane potential were measured with whole
cell patch clamp. Similar to our laboratory's previous results,
hypoxia-induced right ventricular hypertrophy and polycythemia were
blunted in Hif1a(+/) mice. Hypoxia increased PASMC
capacitance in Hif1a(+/+) mice but not in
Hif1a(+/) mice. Chronic hypoxia depolarized and reduced
K+ current density in PASMCs from Hif1a(+/+)
mice. In PASMCs from hypoxic Hif1a(+/) mice, no reduction
in K+ current density was observed, and depolarization was
significantly blunted. Thus partial deficiency of HIF-1 is
sufficient to impair hypoxia-induced depolarization, reduction of
K+ current density, and PASMC hypertrophy.
pulmonary hypertension; voltage-gated potassium current; membrane potential; hypoxia-inducible factor-1; pulmonary arterial smooth muscle cell
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