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Am J Physiol Heart Circ Physiol 284: H1321-H1331, 2003. First published December 27, 2002; doi:10.1152/ajpheart.00795.2002
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Vol. 284, Issue 4, H1321-H1331, April 2003

Protein kinase C-epsilon -null mice have decreased hypoxic pulmonary vasoconstriction

Cassana M. Littler1, Kenneth G. Morris Jr.1, Karen A. Fagan1, Ivan F. McMurtry1, Robert O. Messing3, and Edward C. Dempsey1,2

1 Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, and 2 Denver Veterans Administration Medical Center, Denver, Colorado 80262; and 3 Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, California 94608

PKC contributes to regulation of pulmonary vascular reactivity in response to hypoxia. The role of individual PKC isozymes is less clear. We used a knockout (null, -/-) mouse to test the hypothesis that PKC-epsilon is important in acute hypoxic pulmonary vasoconstriction (HPV). We asked whether deletion of PKC-epsilon would decrease acute HPV in adult C57BL6×SV129 mice. In isolated, salt solution-perfused lung, reactivity to acute hypoxic challenges (0% and 3% O2) was compared with responses to angiotensin II (ANG II) and KCl. PKC-epsilon -/- mice had decreased HPV, whereas responses to ANG II and KCl were preserved. Inhibition of nitric oxide synthase (NOS) with nitro-L-arginine augmented HPV in PKC-epsilon +/+ but not -/- mice. Inhibition of Ca2+-gated K+ channels (KCa) with charybdotoxin and apamin did not enhance HPV in -/- mice relative to wild-type (+/+) controls. In contrast, the voltage-gated K+ channel (KV) antagonist 4-aminopyridine increased the response of -/- mice beyond that of +/+ mice. This suggested that increased KV channel expression could contribute to blunted HPV in PKC-epsilon -/- mice. Therefore, expression of the O2-sensitive KV channel subunit Kv3.1b (100-kDa glycosylated form and 70-kDa core protein) was compared in whole lung and pulmonary artery smooth muscle cell (PASMC) lysates from +/+ and -/- mice. A subtle increase in Kv3.1b was detected in -/- vs. +/+ whole lung lysates. A much greater rise in Kv3.1b expression was found in -/- vs. +/+ PASMC. Thus deletion of PKC-epsilon blunts murine HPV. The decreased response could not be attributed to a general loss in vasoreactivity or derangements in NOS or KCa channel activity. Instead, the absence of PKC-epsilon allows increased expression of KV channels (like Kv3.1b) to occur in PASMC, which likely contributes to decreased HPV.

murine knockout; isolated, perfused lung; pulmonary artery; smooth muscle cells; potassium channels


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