12505875

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4

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 C57BL6xSV129 mice. In isolated, salt solution-perfused lung, reactivity to acute hypoxic challenges (0% and 3% O(2)) 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 Ca(2+)-gated K(+) channels (K(Ca)) with charybdotoxin and apamin did not enhance HPV in -/- mice relative to wild-type (+/+) controls. In contrast, the voltage-gated K(+) channel (K(V)) antagonist 4-aminopyridine increased the response of -/- mice beyond that of +/+ mice. This suggested that increased K(V) channel expression could contribute to blunted HPV in PKC-epsilon -/- mice. Therefore, expression of the O(2)-sensitive K(V) 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 K(Ca) channel activity. Instead, the absence of PKC-epsilon allows increased expression of K(V) channels (like Kv3.1b) to occur in PASMC, which likely contributes to decreased HPV.

eng

IM

MEDLINE

0363-6135

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NLM

H1321-31

pubmed-meshheading:12505875-Angiotensin II, pubmed-meshheading:12505875-Animals, pubmed-meshheading:12505875-Anoxia, pubmed-meshheading:12505875-Calcium, pubmed-meshheading:12505875-Enzyme Inhibitors, pubmed-meshheading:12505875-Female, pubmed-meshheading:12505875-Gene Deletion, pubmed-meshheading:12505875-Lung, pubmed-meshheading:12505875-Mice, pubmed-meshheading:12505875-Mice, Inbred C57BL, pubmed-meshheading:12505875-Mice, Knockout, pubmed-meshheading:12505875-Muscle, Smooth, Vascular, pubmed-meshheading:12505875-Nitric Oxide Synthase, pubmed-meshheading:12505875-Oxygen, pubmed-meshheading:12505875-Potassium Channel Blockers, pubmed-meshheading:12505875-Potassium Channels, pubmed-meshheading:12505875-Potassium Channels, Voltage-Gated, pubmed-meshheading:12505875-Potassium Chloride, pubmed-meshheading:12505875-Protein Kinase C, pubmed-meshheading:12505875-Protein Kinase C-epsilon, pubmed-meshheading:12505875-Pulmonary Artery, pubmed-meshheading:12505875-Shaw Potassium Channels, pubmed-meshheading:12505875-Vasoconstriction

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

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.