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(Circulation Research. 2007;101:1096.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Rescue of cGMP Kinase I Knockout Mice by Smooth Muscle–Specific Expression of Either Isozyme

Silke Weber, Dominik Bernhard, Robert Lukowski, Pascal Weinmeister, René Wörner, Jörg W. Wegener, Nadejda Valtcheva, Susanne Feil, Jens Schlossmann, Franz Hofmann, Robert Feil

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. J.S. is currently at the Institut für Pharmakologie und Toxikologie, Universität Regensburg, Germany.

Correspondence to Dr Franz Hofmann, Institut für Pharmakologie und Toxikologie der Technischen Universität, Biedersteiner Str. 29, D-80802 München, Germany. E-mail hofmann{at}ipt.med.tu-muenchen.de

Smooth muscle expresses the I and the Iß 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 -Iß isozyme to test which isozyme was needed to support basic smooth muscle functions. Mice were generated by gene targeting. The cGKI or the -Iß coding sequences were placed under the control of the SM22 promoter to express either isoform selectively in smooth muscle cells (SM-I or SM-Iß transgene). To generate smooth muscle–specific cGKI or cGKIß rescue mice, the SM-I or SM-Iß transgenes were crossed on a cGKI^–/– genetic background. The levels of cGKI or -Iß expression were comparable to endogenous cGKI expression in wild-type aortic and intestinal smooth muscles. In cGKI or -Iß rescue mice, expression of the isozymes was not detectable in non–smooth muscle tissues and cells. Median survival time of the I and Iß 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 cGKIß 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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cGMP-Dependent Protein Kinase I and Smooth Muscle Relaxation: A Tale of Two Isoforms

Howard K. Surks
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