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

被引:44
作者
Littler, CM
Morris, KG
Fagan, KA
McMurtry, IF
Messing, RO
Dempsey, EC
机构
[1] Univ Colorado, Hlth Sci Ctr, Cardiovasc Pulm Res Lab, Denver, CO 80262 USA
[2] Denver Vet Adm Med Ctr, Denver, CO 80262 USA
[3] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Dept Neurol, Emeryville, CA 94608 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2003年 / 284卷 / 04期
关键词
murine knockout; isolated; perfused lung; pulmonary artery; smooth muscle cells; potassium channels;
D O I
10.1152/ajpheart.00795.2002
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 Ca2+-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.
引用
收藏
页码:H1321 / H1331
页数:11
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