Parakrine Regulation von kardialen Fibroblasten durch lokale natriuretische Peptide
Zusammenfassung der Projektergebnisse
Cardiac remodelling in response to pressure overload or ischemia involves not only cardiomyocyte alterations but also activation of fibroblasts to myofibroblasts and microcirculatory changes. These changes are aggravated by an imbalance of local and systemic neurohumoral factors, finally resulting in impaired cardiac function. Among these factors are the natriuretic peptides (NPs) atrial and B-type (ANP and BNP, mainly released from cardiomyocytes) as well as C-type NP (CNP, secreted by endothelial cells). NPs signal through specific transmembrane guanylyl cyclase (GC) receptors and cyclic GMP as intracellular second messenger: GC-A (the receptor shared by ANP and BNP) and GC-B (for CNP). Our previous experimental studies in genetic mouse models showed that ANP and BNP may act as key local antihypertrophic and proangiogenic factors during pathological cardiac remodelling. The cardiovascular roles of CNP are less well understood. Under physiological conditions, the cardiac levels of CNP are very low, but they markedly and acutely increase in response to cardiac “stress”. Its GC-B receptor is expressed in all resident myocardial cells including fibroblasts, cardiomyocytes and microcirculatory pericytes. Infusions of synthetic, exogenous CNP or of stabilized peptide mimetics had protective antihypertrophic and antifibrotic effects in pre-clinical models of pathological cardiac remodelling. To dissect the paracrine cardiac actions of endogenously formed CNP, we generated novel genetic mouse models with conditional, cell-specific inactivations of the GC-B receptor. Our studies in such mice revealed that local endothelial CNP, elevating intracellular cGMP levels in cardiomyocytes and fibroblasts, targets both components of ventricular diastolic stiffness: it enhances the phosphorylation of titin and thereby titin-based cardiomyocyte distensibility (1); and it counteracts pathological, especially Angiotensin II-mediated fibroblast activation and cardiac fibrosis. Moreover, CNP acts on microcirculatory pericytes and improves their vitality (2) and prevents endothelin-induced contractions (3). Ultimately this attenuates microcirculatory resistance, improves tissue perfusion and diminishes cardiac afterload and work (3). Such cardiac and systemic effects of this endogenous „friend of the heart“ might be exploited for the development of novel therapies for heart failure. In fact, since CNP is the most susceptible of the natriuretic peptides to neprilysin degradation (4), it is possible that this member of the natriuretic peptide family contributes in a significant way to the cardioprotective influence of the dual neprilysin/angiotensin receptor blocker LCZ696 (EntrestoR) in heart failure.
Projektbezogene Publikationen (Auswahl)
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Molecular Physiology of Membrane Guanylyl Cyclase Receptors. Physiol Rev. 2016;96:751- 804
Kuhn M
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Endothelial C-Type Natriuretic Peptide Acts on Pericytes to Regulate Microcirculatory Flow and Blood Pressure. Circulation. 2018;138:494-508
Špiranec K, Chen W, Werner F, Nikolaev VO, Naruke T, Koch F, Werner A, Eder-Negrin P, Diéguez- Hurtado R, Adams RH, Baba HA, Schmidt H, Schuh K, Skryabin BV, Movahedi K, Schweda F, Kuhn M
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An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature. J Clin Endocrinol Metab. 2020;105:2354–66
Lauffer P, Miranda-Laferte E, van Duyvenvoorde HA, van Haeringen A, Werner F, Boudin E, Schmidt H, Mueller TD, Kuhn M, van der Kaay DCM
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C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness. JCI Insight. 2020;5:e139910
Michel K, Herwig M, Werner F, Špiranec Spes K, Abeßer M, Schuh K, Dabral S, Mügge A, Baba HA, Skryabin BV, Hamdani N, Kuhn M
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Heart-Microcirculation Connection: Effects of ANP (Atrial Natriuretic Peptide) on Pericytes Participate in the Acute and Chronic Regulation of Arterial Blood Pressure. Hypertension. 2020a;76:1637-1648
Špiranec Spes K, Chen W, Krebes L, Völker K, Abeßer M, Eder Negrin P, Cellini A, Nickel A, Nikolaev VO, Hofmann F, Schuh K, Schweda F, Kuhn M
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Natriuretic Peptides Attenuate Retinal Pathological Neovascularization Via Cyclic Guanosine Monophosphate Signaling in Pericytes and Astrocytes. Arterioscler Thromb Vasc Biol. 2020b;40:159-174
Špiranec Spes K, Hupp S, Werner F, Koch F, Völker K, Krebes L, Kämmerer U, Heinze KG, Braunger BM, Kuhn M
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Skeletal muscle derived Musclin protects the heart during pathological overload. Nat Commun. 2022;13:149
Szaroszyk M, Kattih B, Martin-Garrido A, Trogisch FA, Dittrich GM, Grund A, Abouissa A, Derlin K, Meier M, Holler T, Korf-Klingebiel M, Völker K, Garfias Macedo T, Pablo Tortola C, Boschmann M, Huang N, Froese N, Zwadlo C, Malek Mohammadi M, Luo X, Wagner M, Cordero J, Geffers R, Batkai S, Thum T, Bork N, Nikolaev VO, Müller OJ, Katus HA, El-Armouche A, Kraft T, Springer J, Dobreva G, Wollert KC, Fielitz J, von Haehling S, Kuhn M, Bauersachs J, Heineke J
