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1 Cardiovascular Pulmonary Research, University of Colorado Health Sciences Center, Denver, CO, USA
2 Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, CA, USA
3 Cardiovascular Pulmonary Research, University of Colorado Health Sciences Center, Denver, CO, USA; Denver Veterans Administration Medical Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: edward.dempsey{at}uchsc.edu.
Protein kinase C (PKC) contributes to the regulation of pulmonary vascular reactivity in response to hypoxia. The role of individual PKC isozymes is less clear. We used a knockout (null, -/-) mouse approach to test the hypothesis that PKC-epsilon (
) is important in acute hypoxic pulmonary vasoconstriction (HPV). We asked if deletion of PKC- would decrease acute HPV in adult C57BL6xSV129 mice. Using an isolated salt-solution-perfused lung, reactivity to acute hypoxic challenges (0 and 3% oxygen) was compared with responses to angiotensin-II (A-II) and potassium chloride (KCl). PKC- -/- mice had decreased HPV, while responses to A-II and KCl were preserved. Inhibition of nitric oxide synthase (NOS) with nitro-L-arginine augmented HPV in PKC- +/+, but not -/-, mice. Inhibition of calcium-gated potassium channels (KCa) with charybdotoxin and apamin did not enhance HPV in -/- mice relative to wild type (+/+) controls. In contrast, the voltage-gated potassium channel (KV) antagonist, 4-aminopyridine, increased the response of -/- mice beyond that of +/+ controls. This finding suggested that increased KV channel expression could contribute to the blunted HPV of PKC- -/- mice. To investigate this possibility, expression of the oxygen-sensitive KV channel subunit Kv3.1b (100kDa glycosylated form and 70kDa core protein) was compared in whole lung and pulmonary artery smooth muscle cells (PA SMC) lysates from +/+ and -/- mice. A subtle increase in Kv3.1b was detected in -/- whole lung lysates compared with +/+ controls. A much greater rise in Kv3.1b expression was found in -/- PA SMC compared with +/+ controls. Thus, deletion of PKC- 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- allows increased expression of KV channels (like Kv3.1b) to occur in PA SMC which likely contributes to decreased HPV.
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