19066
2016
eng
16
2
111
article
1
2019-10-28
--
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Endothelial actions of atrial natriuretic peptide prevent pulmonary hypertension in mice
The cardiac hormone atrial natriuretic peptide (ANP) regulates systemic and pulmonary arterial blood pressure by activation of its cyclic GMP-producing guanylyl cyclase-A (GC-A) receptor. In the lung, these hypotensive effects were mainly attributed to smooth muscle-mediated vasodilatation. It is unknown whether pulmonary endothelial cells participate in the homeostatic actions of ANP. Therefore, we analyzed GC-A/cGMP signalling in lung endothelial cells and the cause and functional impact of lung endothelial GC-A dysfunction. Western blot and cGMP determinations showed that cultured human and murine pulmonary endothelial cells exhibit prominent GC-A expression and activity which were markedly blunted by hypoxia, a condition known to trigger pulmonary hypertension (PH). To elucidate the consequences of impaired endothelial ANP signalling, we studied mice with genetic endothelial cell-restricted ablation of the GC-A receptor (EC GC-A KO). Notably, EC GC-A KO mice exhibit PH already under resting, normoxic conditions, with enhanced muscularization of small arteries and perivascular infiltration of inflammatory cells. These alterations were aggravated on exposure of mice to chronic hypoxia. Lung endothelial GC-A dysfunction was associated with enhanced expression of angiotensin converting enzyme (ACE) and increased pulmonary levels of Angiotensin II. Angiotensin II/AT(1)-blockade with losartan reversed pulmonary vascular remodelling and perivascular inflammation of EC GC-A KO mice, and prevented their increment by chronic hypoxia. This experimental study indicates that endothelial effects of ANP are critical to prevent pulmonary vascular remodelling and PH. Chronic endothelial ANP/GC-A dysfunction, e.g. provoked by hypoxia, is associated with activation of the ACE-angiotensin pathway in the lung and PH.
Basic Research in Cardiology
10.1007/s00395-016-0541-x
urn:nbn:de:bvb:20-opus-190664
Basic Research in Cardiology (2016) 111:22, 16 Seiten. https://doi.org/10.1007/s00395-016-0541-x
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Franziska Werner
Baktybek Kojonazarov
Birgit Gaßner
Marco Abeßer
Kai Schuh
Katharina Völker
Hideo A. Baba
Bhola K. Dahal
Ralph T. Schermuly
Michaela Kuhn
eng
uncontrolled
Atrial natriuretic peptide
eng
uncontrolled
Endothelium
eng
uncontrolled
Guanylyl cyclase-A
eng
uncontrolled
Cyclic GMP
eng
uncontrolled
Pulmonary hypertension
Medizin und Gesundheit
open_access
Physiologisches Institut
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/19066/Werner_BasicResearchInCardiology_2016.pdf
17632
2018
eng
103
17
article
1
2019-02-11
--
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β Cell-specific deletion of guanylyl cyclase A, the receptor for atrial natriuretic peptide, accelerates obesity-induced glucose intolerance in mice
Background:
The cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and β-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells.
Methods:
Mice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in β-cells (β GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. β-cell size and number were measured by immunofluorescence-based islet morphometry.
Results:
In vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and β-cell morphology were similar in β GC-A KO mice and control littermates. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation.
Conclusions:
Our studies of β GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate β-cell's growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of β-cells to HFD-induced obesity. Impaired β-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.
Cardiovascular Diabetology
10.1186/s12933-018-0747-3
urn:nbn:de:bvb:20-opus-176322
Cardiovascular Diabetology (2018) 17:103. DOI: 10.1186/s12933-018-0747-3
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Sabine Tauscher
Hitoshi Nakagawa
Katharina Völker
Franziska Werner
Lisa Krebes
Tamara Potapenko
Sören Doose
Andreas L. Birkenfeld
Hideo A. Baba
Michaela Kuhn
eng
uncontrolled
cylic GMP
eng
uncontrolled
guanylyl cyclase-A
eng
uncontrolled
insulin
eng
uncontrolled
natriuretic peptides
eng
uncontrolled
obesity
eng
uncontrolled
β-cells
Medizin und Gesundheit
open_access
Physiologisches Institut
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17632/Tauscher_Cardiovascular_Diabetology.pdf
12656
2012
eng
141–151
1
93
article
1
2016-02-01
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--
Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway
Aims
Cardiac atrial natriuretic peptide (ANP) participates in the maintenance of arterial blood pressure and intravascular volume homeostasis. The hypovolaemic effects of ANP result from coordinated actions in the kidney and systemic microcirculation. Hence, ANP, via its guanylyl cyclase-A (GC-A) receptor and intracellular cyclic GMP as second messenger, stimulates endothelial albumin permeability. Ultimately, this leads to a shift of plasma fluid into interstitial pools. Here we studied the role of caveolae-mediated transendothelial albumin transport in the hyperpermeability effects of ANP.
Methods and results
Intravital microscopy studies of the mouse cremaster microcirculation showed that ANP stimulates the extravasation of fluorescent albumin from post-capillary venules and causes arteriolar vasodilatation. The hyperpermeability effect was prevented in mice with conditional, endothelial deletion of GC-A (EC GC-A KO) or with deleted caveolin-1 (cav-1), the caveolae scaffold protein. In contrast, the vasodilating effect was preserved. Concomitantly, the acute hypovolaemic action of ANP was abolished in EC GC-A KO and Cav-1−/− mice. In cultured microvascular rat fat pad and mouse lung endothelial cells, ANP stimulated uptake and transendothelial transport of fluorescent albumin without altering endothelial electrical resistance. The stimulatory effect on albumin uptake was prevented in GC-A- or cav-1-deficient pulmonary endothelia. Finally, preparation of caveolin-enriched lipid rafts from mouse lung and western blotting showed that GC-A and cGMP-dependent protein kinase I partly co-localize with Cav-1 in caveolae microdomains.
Conclusion
ANP enhances transendothelial caveolae-mediated albumin transport via its GC-A receptor. This ANP-mediated cross-talk between the heart and the microcirculation is critically involved in the regulation of intravascular volume.
Cardiovascular Research
10.1093/cvr/cvr279
urn:nbn:de:bvb:20-opus-126562
Lizenzhinweis: The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for noncommercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated.
Cardiovascular Research (2012) 93, 141–151 doi:10.1093/cvr/cvr279
Deutsches Urheberrecht
Wen Chen
Birgit Gaßner
Sebastian Börner
Viacheslav O. Nikolaev
Nicolas Schlegel
Jens Waschke
Nadine Steinbronn
Ruth Strasser
Michaela Kuhn
eng
uncontrolled
caveolin-1
eng
uncontrolled
microvessel permeability
eng
uncontrolled
atrial natriuretic peptide
Medizin und Gesundheit
open_access
Pathologisches Institut
Institut für Pharmakologie und Toxikologie
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12656/141.full.pdf
13469
2013
eng
1233–1244
34
article
1
2016-06-11
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Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I
Aims: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism.
Methods and results: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the \([Ca^{2+}]_i\)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte \(Ca^{2+}_i\) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, \(Ca^{2+}_i\)-handling, and contractility via cGKI.
Conclusion: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte \(Ca^{2+}_i\) handling and contractility.
European Heart Journal
urn:nbn:de:bvb:20-opus-134693
European Heart Journal (2013) 34, 1233–1244 doi:10.1093/eurheartj/ehr445
Stefan Frantz
Michael Klaiber
Hideo A. Baba
Heinz Oberwinkler
Katharina Völker
Birgit Gaßner
Barbara Bayer
Marco Abeßer
Kai Schuh
Robert Feil
Franz Hofmann
Michaela Kuhn
eng
uncontrolled
cyclic
eng
uncontrolled
GMPcGMP-dependent protein kinase I
eng
uncontrolled
cardiac hypertrophy
eng
uncontrolled
natriuretic peptide
eng
uncontrolled
Ca2+i handling
Medizin und Gesundheit
open_access
Physiologisches Institut
Medizinische Klinik und Poliklinik I
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13469/146_Frantz_European_Heart.pdf