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

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Abstract
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-ε is important in acute hypoxic pulmonary vasoconstriction (HPV). We asked whether deletion of PKC-ε 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-ε −/− 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-ε +/+ 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-ε −/− 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-ε 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-ε allows increased expression of KV channels (like Kv3.1b) to occur in PASMC, which likely contributes to decreased HPV.

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