| 12505875 |
Littler CM, Morris KG Jr, Fagan KA, McMurtry IF, Messing RO, Dempsey EC: Protein kinase C-epsilon-null mice have decreased hypoxic pulmonary vasoconstriction. Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1321-31. Epub 2002 Dec 27.
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. |
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