General information and structure
Our research activities are in the field of cardiovascular physiology and pathophysiology. Our investigation has focused on understanding the molecular mechanisms associated with specific forms of arterial hypertension and cardiac hypertrophic remodeling. Another major point of interest is the function of SPRED proteins in cellular proliferation and differentiation. In particular, by application of gene targeting technology in mice we obtained new insights into the diverse physiological functions of natriuretic peptides, nitric oxide (NO) and their guanylyl cyclase (GC) receptors as well as of SPRED proteins. These different projects are supported by the DFG (SFB 688 and 487 besides personal fundings) and the IZKF Würzburg.
Main research focus
1. Endothelial effects of the cardiac hormone atrial natriuretic peptide (ANP)
(M. Kuhn, B. Gaßner, W. Chen, K. Schwarz and coworkers)
The cardiac hormone atrial natriuretic peptide (ANP), via its vasodilating and diuretic effects, has an important physiological role in the maintenance of arterial blood pressure and volume. Its guanylyl cyclase-A (GC-A) receptor is highly expressed in vascular endothelium, but the functional relevance of this is controversial. To dissect the endothelium-mediated actions of ANP in vivo, we inactivated the GC-A gene selectively in endothelial cells. Mice with endothelium-restricted GC-A deletion exhibited reduced vascular permeability to plasma protein, resulting in chronically increased plasma volume, arterial hypertension and cardiac hypertrophy. Renal excretion and vasodilation did not account for these changes. Thus ANP-induced increases in endothelial permeability may be critical to the ability of ANP to lower arterial blood pressure. Our current studies supported by the SFB 688 are directed to dissect the cellular pathways mediating these effects.
2. Posttranslational modifications of the ANP receptor
(M. Kuhn, M. Hartmann, J. Schröter, A. Gazinski and coworkers)
In some forms of arterial hypertension and as one of the earliest and pathognomonic events in cardiac hypertrophy and insufficiency, the cardiac synthesis and release of ANP is markedly enhanced, but the cardiovascular effects are clearly diminished, indicating a receptor or postreceptor defect of GC-A. Biochemical studies in transfected GC-A–overexpressing cells showed that phosphorylation of GC-A within the intracellular domain is essential for its activation process. In turn, desensitization and/or inactivation of GC-A probably involves ANP-dependent dephosphorylation of GC-A. Notably, the responsiveness of GC-A to ANP is also reduced by exposure to growth hormones such as Angiotensin II and endothelin and in vitro this correlates with receptor dephosphorylation. In collaboration with Professor Albert Sickmann (Protein Mass Spectrometry, Rudolf-Virchow-Center) our project in the SFB 487 attempts to identify (in)activating modifications of GC-A and the mediating regulatory proteins.
3. Cardiac effects of ANP
(M. Kuhn, K. Völker, M. Klaiber and coworkers)
Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Cardiac myocytes have signaling pathways that agonize and antagonize hypertrophic growth. In chronic hemodynamic overload, there is a significant increase in ANP expression in the cardiac ventricles. Our studies in cultured myocytes and genetically engineered mice showed that in this situation the ANP / GC-A pathway exerts not only endocrine but also local antihypertrophic actions (Figure 1). The molecular mechanism(s) by which ANP and GC-A inhibit cardiac hypertrophy is not definitively known. Our observations suggest that ANP modulates myocyte intracellular pH and [Ca2+] homeostasis and counter-regulates calcium-dependent hypertrophic signaling pathways such as CaMKII and calcineurin.
Physiology and pathophysiology (together with Chair II) for the students of medicine, dentistry, pharmacy, psychology, and informatics (lectures, seminars, integrated seminars, and practical courses as well as examinations).
- Kuhn M (2009) Function and dysfunction of Mammalian membrane guanylyl cyclase receptors: lessons from genetic mouse models and implications for human diseases. Handb Exp Pharmacol. 191: 47-69.
- Hartmann M, Skryabin BV, Müller T, Gazinski A, Schröter J, Gassner B, Nikolaev VO, Bünemann M, Kuhn M (2008) Alternative splicing of the guanylyl cyclase-A receptor modulates atrial natriuretic peptide signaling. J Biol Chem. 283(42): 28313-28320.
- Schreier B, Börner S, Völker K, Gambaryan S, Schäfer SC, Kuhlencordt P, Gassner B, Kuhn M (2008) The heart communicates with the endothelium through the guanylyl cyclase-A receptor: acute handling of intravascular volume in response to volume expansion. Endocrinology 149(8): 4193-4199.
- Sabrane K, Kruse MN, Fabritz L, Zwiener M, Zetsche B, Skryabin BV, Baba HA, Yanagisawa M, Kuhn M (2005) Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide. J Clin Invest. 115: 1666-1674.
- Kilic A, Velic A, De Windt L,J, Fabritz L, Voß M, Mitko D, Zwiener M, Baba HA, van Eickels M, Schlatter E, Kuhn M (2005) Enhanced activity of the myocardial Na+/H+ exchanger NHE-1 contributes to cardiac remodeling in ANP – receptor deficient mice. Circulation 112, 2307-2317.
- Yurukova S, Kilic A, Völker K, Leineweber K, Dybkova N, Maier LS, Brodde O-E, Kuhn M (2007) CamKII – mediated increased lusitropic responses to ß-adrenoreceptor stimulation in ANP – receptor deficient mice. Cardiovasc Res 73(4), 678-688.
- Kilic A, Bubikat, A, Gaßner B, Baba H.A., Kuhn M (2007) Local actions of atrial natriuretic peptide counteract angiotensin II stimulated cardiac remodeling. Endocrinology 148, 4162-4169.
- Bundschu K, Walter U, Schuh K (20007) Getting a first clue about SPRED functions. BioEssays 29, 897–907.