A Pfeifer

AK Singh

Beate Spießberger

Franz Hofmann

Jens Schlossmann

M Föller

Pascal Weinmeister

Robert Lukowski

S Weber

BMC Pharmacology

English

PubMed

Crossref

BioMed Central
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BMC Pharmacology
Open AccessOral presentation
Rescue of cGMP kinase I and the cause of premature death
Franz Hofmann*, Robert Lukowski, Beate Spießberger, Jens Schlossmann 
and Pascal Weinmeister
Address: Institut für Pharmakologie und Toxikologie der TU München, Biedersteiner Str. 29, D-80802 München, Germany
Email: Franz Hofmann* - hofmann@lrz.tum.de
* Corresponding author    
Background
50% of mice with a classical deletion of the cGK Iá and Iβ
gene (cGKI-/-) die at 6 weeks [1] whereas 50% of cGK Iα
and Iβ rescue mice (RM) survive until one year [2]. Here,
we investigated the reason(s) for the premature death of
the different gene-targeted cGKI animals.
Results
cGKI-/- and the RM have a severe anemia and splenomeg-
alie which is associated with a strongly reduced iron con-
tent and expression of the ferritin light chain in the spleen.
Furthermore, the mRNA levels of transferrin receptor
(TfRc) and divalent metal ion transporter (DMT1) are
increased in the spleen. Oral or i.m. administration of
iron restores partially the iron levels in the spleen of gene-
targeted cGKI mice, but affects the anemia only moder-
ately. Examination of the intestinal tract showed a mas-
sive ulceration in the duodenum that caused intestinal
bleeding in cGKI-/- and at the later age in the RM as well.
The cGKI protein was expressed in smooth muscle cells of
all intestinal sections including the duodenum of RM.
However, H+ induced duodenal HCO3- secretion was
severely reduced in the cGKI-/- and RM. HCO3- secretion
was measured as described in [3]. Interestingly, the duo-
denal HCO3- secretion was not affected by targeted dele-
tion of the cGKI gene in the secretory epithel or in Cajal
cells. In line with this result, we did not detect the cGKI
protein by extensive immuno-cytochemical analysis in
the secretory epithel or Cajal cells.
Conclusion
These results confirm previous observations that cGKI
confers antiapoptotic/prosurvival function to erythrocytes
[4]. In addition, we propose that cGKI-/- and RM die
because of the massive intestinal bleedings caused by an
ulceration of the duodenum. We conclude that the cGMP/
cGKI pathway it is essential for H+ induced secretion of
HCO3- thereby protecting the small intestine from gastric
acid injury.
Acknowledgements
We thank Mrs. Kenell and Mrs. Brummer for invaluable help. Dr. Dieter 
Saur and Florian Greten for providing Cre-mice and Ute Seidler for the 
duodenal bicarbonate secretion measurement.
References
1. Pfeifer A, Klatt P, Massberg S, Ny L, Sausbier M, Hirneiß C, Wang G,
Korth M, Aszódi A, Andersson E, Krombach F, Mayerhofer A, Ruth
P, Fässler R, Hofmann F: Defective smooth muscle regulation in
cGMP kinase I-deficient mice.  EMBO J 1998, 17:3045-3051.
2. Weber S, Bernhard D, Lukowski R, Weinmeister P, Wörner R,
Wegener JW, Feil S, Schlossmann J, Hofmann F, Feil R: Rescue of
cGMP kinase I knockout mice by smooth muscle specific
expression of either isozyme.  Circ Res 2007, 101:1096-1103.
3. Singh AK, Sjöblom M, Zheng W, Krabbenhöft A, Riederer B, Rausch
B, Manns MP, Soleimani M, Seidler U: CFTR and its key role in in
vivo resting and luminal acid-induced duodenal HCO3-
secretion.  Acta Physiol (Oxf) 2008, 193:357-365.
4. Föller M, Feil S, Ghoreschi K, Koka S, Gerling A, Thunemann M, Hof-
mann F, Schuler B, Vogel J, Pichler B, Kasinathan RS, Nicolay JP, Huber
SM, Lang F, Feil R: Anemia and splenomegaly in cGKI-deficient
mice.  Proc Natl Acad Sci USA 2008, 105:6771-6776.
from 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications
Regensburg, Germany. 19–21 June 2009
Published: 11 August 2009
BMC Pharmacology 2009, 9(Suppl 1):S15 doi:10.1186/1471-2210-9-S1-S15
<supplement> <title> <p>4th International Conference of cGMP Generators, Effectors and Therapeutic Implications</p> </title> <note>Meeting abstracts – A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1471-2210-9-S1-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1471-2210-9-S1-info.pdf</url> </supplement>
This abstract is available from: http://www.biomedcentral.com/1471-2210/9/S1/S15
© 2009 Hofmann et al; licensee BioMed Central Ltd. 


Rescue of cGMP kinase I and the cause of premature death

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Anemia and splenomegaly in cGKI-deficient mice.

F: Defective smooth muscle regulation in cGMP kinase I-deficient mice.

Feil R: Rescue of cGMP kinase I knockout mice by smooth muscle specific expression of either isozyme. Circ Res

U: CFTR and its key role in in vivo resting and luminal acid-induced duodenal HCO3-secretion. Acta Physiol (Oxf)

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Rescue of cGMP kinase I and the cause of premature death

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