Published online before print September 27, 2007, doi: 10.1161/CIRCRESAHA.107.154351
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Submitted on April 16, 2007
Revised on September 4, 2007
Accepted on September 13, 2007
Rescue of cGMP Kinase I Knockout Mice by Smooth Muscle–Specific Expression of Either Isozyme
Silke Weber ;
From the Institut für Pharmakologie und Toxikologie der Technischen Universität (S.W., D.B., R.L., P.W., R.W., J.W.W., J.S., F.H.), München; Interfakultäres Institut für Biochemie (N.V., S.F., R.F.), Universität Tübingen, Germany. Present address for J.S.: Institut für Pharmakologie und Toxikologie, Universität Regensburg, Germany.
* To whom correspondence should be addressed. E-mail: hofmann{at}ipt.med.tu-muenchen.de.
Smooth muscle expresses the I
and the I
isoforms of cGMP-dependent protein kinase I (cGKI). Inactivation of the murine cGKI gene prkg1 leads to multiple phenotypes and premature death at 
6 weeks. We reconstituted mice with the cGKI or -I isozyme to test which isozyme was needed to support basic smooth muscle functions. Mice were generated by gene targeting. The cGKI or the -I coding sequences were placed under the control of the SM22 promoter to express either isoform selectively in smooth muscle cells (SM-I or SM-I transgene). To generate smooth muscle–specific cGKI or cGKI rescue mice, the SM-I or SM-I transgenes were crossed on a cGKI-/- genetic background. The levels of cGKI or -I expression were comparable to endogenous cGKI expression in wild-type aortic and intestinal smooth muscles. In cGKI or -I rescue mice, expression of the isozymes was not detectable in non–smooth muscle tissues and cells. Median survival time of the I and I rescue mice was 52 weeks. Both isozymes mediated the 8-bromo-cGMP–induced relaxation of precontracted jejunum and aorta muscle strips. Activation of both isozymes reduced hormone- or K+-induced [Ca2+]i levels. The cGKI and cGKI rescue mice did not show a significant difference in intestinal passage time of BaSO4 in comparison with wild-type animals. Telemetric blood pressure measurements in conscious freely moving animals did not show differences between rescues and control mice in basal blood pressure and its regulation by DETA-NO, sodium nitroprusside, carbachol, or Y-27632. These results show that cGKI in smooth muscle is essential and that either cGKI isozyme alone can rescue basic vascular and intestinal smooth muscle functions.
Key words: cGMP kinase isozymes • PKG • nitric oxide • smooth muscle • blood pressure
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