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(Circulation Research. 2003;93:e143.)
© 2003 American Heart Association, Inc.

Letter to the Editor

Alternative Splicing of cGMP-Dependent Protein Kinase I and Nitrate Tolerance

Robert Feil, Franz Hofmann

Institut für Pharmakologie und Toxikologie, Technische Universität, München, Germany, feil@ipt.med.tu-muenchen.de

An extract of the first 250 words of the full text is provided, because this article has no abstract.

To the Editor:

A major point of the recent study by Gerzanich et al¹ is that angiotensin II–induced "alternative splicing of cGKI [cGMP-dependent protein kinase I] represents a novel mechanism for reducing sensitivity to NO/cGMP" (page 805).

This conclusion was based on the authors’ finding of "a large increase in cGKIß mRNA and a decrease in cGKI mRNA" (page 805) in basilar arteries of angiotensin II–hypertensive versus control rats (their Figure 5). The cGKI and cGKIß proteins differ only in their amino-terminal regions (approximately the first 100 amino acids), which are encoded by alternatively spliced exons of the cGKI gene.² Alternative splicing resulting in upregulation of cGKIß, which is less sensitive to cGMP activation than cGKI, might well be a mechanism contributing to nitrate tolerance of vascular smooth muscle. The authors claim to measure relative mRNA levels for cGKI and cGKIß by reverse transcription (RT)-PCR and Northern blot analysis using probes unique for each isoform mRNA. However, our inspection of the PCR primers used in this study and of the rat genomic cGKI locus revealed that the amplicons detected in the PCR experiments do not correspond to the known mRNA/cDNA sequence of the cGKI or cGKIß isoform but to intronic DNA sequences of the rat cGKI locus. Similarly, the probe used for Northern blot detection of the cGKI mRNA corresponds to intronic DNA, and only part of the cGKIß probe is complementary to the cGKIß mRNA, the rest corresponding to intronic sequences. It is not clear why the authors . . . [Full Text of this Article]