Published Online
on March 3, 2008

A more recent version of this article appeared on March 18, 2008

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Submitted on January 16, 2007
Accepted on January 23, 2008

Heart-Specific Ablation of Prkar1a Causes Failure of Heart Development and Myxomagenesis

Zhirong Yin MD, PhD, Georgette N. Jones BS, William H. Towns II BS, Xiaoli Zhang PhD, E. Dale Abel MBBS, DPhil, Philip F. Binkley MD, MPH, David Jarjoura PhD, and Lawrence S. Kirschner MD, PhD^*

From the Department of Molecular Virology, Immunology, and Molecular Genetics (Z.Y., G.N.J., W.H.T., L.S.K.), Center for Biostatistics (X.Z., D.J.), Division of Cardiology (P.F.B.), and Division of Endocrinology, Diabetes, and Metabolism (L.S.K.), Ohio State University, Columbus, and Division of Endocrinology Metabolism and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City (E.D.A.).

^* To whom correspondence should be addressed. E-mail: Lawrence.Kirschner{at}osumc.edu.

Background—Protein kinase A signaling has long been known to play an important role in cardiac function. Dysregulation of the protein kinase A system, caused by mutation of the protein kinase A regulatory subunit gene PRKAR1A, causes the inherited tumor syndrome Carney complex, which includes cardiac myxomas as one of its cardinal features. Mouse models of this genetic defect have been unsatisfactory because homozygote null animals die early in development and heterozygotes do not exhibit a cardiac phenotype.

Methods and Results—To study the cardiac-specific effects resulting from complete loss of Prkar1a, we used cre-lox technology to generate mice lacking this protein specifically in cardiomyocytes. Conditional knockout mice died at day 11.5 to 12.5 of embryogenesis with thin-walled, dilated hearts. These hearts showed elevated protein kinase A activity and decreased cardiomyocyte proliferation before demise. Analysis of the expression of transcription factors required for cardiogenesis revealed downregulation of key cardiac transcription factors such as the serum response factor, Gata4, and Nkx2–5. Although heart wall thickness was reduced overall, specific areas exhibited morphological changes consistent with myxomatous degeneration in the walls of knockout hearts.

Conclusions—Loss of Prkar1a from the heart causes a failure of proper myocardial development with subsequent cardiac failure and embryonic demise. These changes appear to be due to suppression of cardiac-specific transcription by increased protein kinase A activity. These biochemical changes lead to myxoma-like changes, indicating that these mice may be a good model with which to study the formation of these tumors.

Key words: cardiomyopathy • cyclic AMP-dependent protein kinases • genes • myxoma • signal transduction

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Clinical Summaries
Circulation 2008 117: 1353. [Extract] [Full Text]

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