of the Max - MDC

Cardiovascular Hormones
Michael Bader
The group is interested in the molecular biology and function of hormone systems involved in
cardiovascular regulation. Besides the cloning and characterization of genes for the components,
the physiological functions of the systems are analyzed by the production and analysis of
transgenic and gene-targeted animal models.
Renin-angiotensin system
Natalia Alenina, Brit Rentzsch, Mihail Todiras, Ping Xu,
Celine Burckle, Philip Boyé, Cibele Cardoso, Gabin Sihn,
Markus May, Anna Panek
The renin-angiotensin system (RAS) is of central importance
in blood pressure regulation and in the initiation of target
organ damage. In particular, local angiotensin-II generating
systems in tissues such as brain, heart, and kidney are
involved in these processes. Therefore, transgenic rats with
local up- or downregulation of RAS components in brain,
heart, and vessels, e.g. by the organ-specific expression of
antisense-RNA or of a peptide-liberating protein, were produced.
Using these rats we could show that central
angiotensin modulates circadian blood pressure rhythms,
the baroreceptor reflex and, as non-cardiovascular parameters,
alcohol consumption and behaviour. Furthermore, it is
involved in the hypertensive and hypertrophic effects of circulating
angiotensin. Other genetically altered mouse and
rat models for non-classical RAS components such as ACE2,
the renin receptor, the Mas protooncogene, and angiotensin(1-7)
have elucidated the physiological function of
these factors. Knockout mice for the Mas protooncogene
revealed its function as receptor for angiotensin(1-7).
Together with transgenic rats overexpressing this peptide by
the use of a peptide-liberating protein, Mas-knockout mice
characterized the angiotensin(1-7)/Mas system as a cardioprotective
axis that counteracts the classical RAS effects.
Kallikrein-kinin system
Ines Schadock, Marcelo Mori, Edson Santos, Regiane
Sabatini, Aline Hilzendeger, Vanessa Merino, Marcos
Barbosa, Robert Fischer, Fatimunnisa Qadri
The kallikrein-kinin system (KKS) is an important hormone
system for cardiovascular regulation also mostly counteracting
the effects of the RAS. As models for the functional
analysis of the KKS in intact animals, transgenic rats were
generated expressing different components of the system,
such as tissue kallikrein, the kinin B1 or the B2 receptor
either ubiquitously or specifically in cardiovascular organs.
These animals supported the protective role of the KKS in
kidney and heart against ischemic, diabetic, and hypertrophic
injury. Knockout mice for the kinin B1 receptor were
generated and revealed important functions of this protein
in pain perception and inflammation. The close opposition
of the two kinin receptor genes, B1 and B2, on one chromosome
prohibited the generation of double knockout animals
by simple breeding. Thus, we had to target the B1 gene
again in ES-cells isolated from B2-knockout mice in order
generate animals lacking both kinin receptors and thereby
being devoid of a functional KKS. These mice were completely
normal at baseline suggesting that the KKS is irrelevant
for development and basic regulation of the cardiovascular
system, but they did not develop hypotension after
treatment with a bacterial toxin. Together with corresponding
data of a transgenic rat overexpressing the B1 receptor
in endothelial cells these results showed that the KKS and
particularly B1 receptors in endothelial cells are essential
for the hypotension occurring during septic shock.
Natriuretic peptide system
Jens Buttgereit
There are 3 natriuretic peptides (NP), ANP, BNP, and CNP,
which interact with two natriuretic peptide receptors, NPR-A
and NPR-B, to induce a multitude of actions in heart, kidney,
vessels and other tissues. The receptors are dimeric
molecules, which after activation synthesize cyclic GMP. We
have shown that dimerization is essential for the activation
of the receptors and have designed dominant negative
mutants to downregulate the activity of the receptors in
cells and transgenic animals. A first transgenic rat model
with ubiquitous expression of a dominant negative mutant
for NPR-B develops cardiac hypertrophy already at baseline
and exhibits an exaggerated response to volume overload
supporting a cardioprotective action of this receptor and its
ligand CNP. Moreover, these animals show an impaired bone
growth in accordance with the phenotype of knockout mice
for NPR-B and CNP.
Cardiovascular and Metabolic Disease Research 11