Local, fibroblast-specific cardiac actions of the natriuretic peptides ANP, BNP and CNP

利钠肽 ANP、BNP 和 CNP 的局部、成纤维细胞特异性心脏作用

• 批准号: 322613005
• 负责人: Professorin Dr. Michaela Kuhn
• 金额: --
• 依托单位: Physiologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/322613005?language=en
• 关键词: Local; fibroblast; specific; cardiac; actions

Cardiac remodeling in response to pressure overload or ischemia involves not only cardiomyocyte alterations but also activation of fibroblasts to myofibroblasts and excessive collagen accumulation contributing to impaired cardiac function. These changes are modulated by mechanical forces and neurohumoral factors. Among these factors are the natriuretic peptides atrial and B type (ANP and BNP, mainly released from myocytes) as well as C type NP (CNP, secreted by endothelial and infiltrating inflammatory cells). NPs signal through specific transmembrane guanylyl cyclase (GC) receptors and cyclic GMP as second messenger, namely 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 cardiac remodeling. The cardiac role of CNP is less well understood. Its GC B receptor is expressed in all resident myocardial cells (fibroblasts, cardiomyocytes and vascular cells). Administration of synthetic CNP greatly attenuates cardiac hypertrophy, fibrosis and contractile dysfunction in mice with experimental pressure overload or ischemia. Notably, our ongoing studies of a novel genetic mouse model with cardiomyocyte restricted deletion of GC B indicate that myocytes are only partly involved in these protective CNP actions. In vitro, synthetic NPs (CNP more than ANP) counterregulate the stimulatory effects of TGF on fibroblast proliferation, differentiation and collagen secretion. To dissect the fibroblast actions of endogenous local NPs in vivo, here we generate new genetic models with induced, fibroblast specific deletion of either GC A or GC B in adult mice for studies of the impact on hypertensive or ischemic heart disease.

压力过载或缺血时的心脏重塑不仅涉及心肌细胞的改变，还涉及成纤维细胞向肌成纤维细胞的活化和过多的胶原积累，从而导致心功能受损。这些变化是由机械力和神经体液因素调节的。这些因子包括心房和B型钠肽（ANP和BNP，主要由肌细胞释放）以及C型NP （CNP，由内皮细胞和浸润性炎症细胞分泌）。NPs通过特定的跨膜观酰基环化酶（GC）受体和环GMP作为第二信使，即GC A （ANP和BNP共享的受体）和GC B （CNP）发出信号。我们之前在遗传小鼠模型中的实验研究表明，ANP和BNP可能是心脏重构过程中关键的局部抗肥厚和促血管生成因子。CNP在心脏中的作用尚不清楚。其GC - B受体在所有常驻心肌细胞（成纤维细胞、心肌细胞和血管细胞）中表达。合成CNP可显著减轻实验性压力过载或缺血小鼠的心肌肥厚、纤维化和收缩功能障碍。值得注意的是，我们正在进行的心肌细胞GC B限制性缺失的新型遗传小鼠模型研究表明，心肌细胞仅部分参与这些保护性CNP作用。在体外，合成NPs （CNP多于ANP）可拮抗TGF对成纤维细胞增殖、分化和胶原分泌的刺激作用。为了在体内解剖内源性局部NPs的成纤维细胞作用，我们在成年小鼠中建立了新的遗传模型，诱导成纤维细胞特异性缺失GC A或GC B，用于研究对高血压或缺血性心脏病的影响。

项目成果

An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature

• DOI: 10.1210/clinem/dgaa190
• 发表时间: 2020-07-01
• 期刊: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
• 影响因子: 5.8
• 作者: Lauffer, Peter;Miranda-Laferte, Erick;van der Kaay, Danielle C. M.
• 通讯作者: van der Kaay, Danielle C. M.

Heart-Microcirculation Connection

心脏-微循环连接

• DOI: 10.1161/hypertensionaha.120.15772
• 期刊: Hypertension
• 影响因子: 8.3
• 作者: 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
• 通讯作者: Kuhn M

Natriuretic Peptides Attenuate Retinal Pathological Neovascularization Via Cyclic GMP Signaling in Pericytes and Astrocytes.

• DOI: 10.1161/atvbaha.119.313400
• 发表时间: 2019-04
• 期刊: Arteriosclerosis, Thrombosis, & Vascular Biology
• 作者: Katarina Špiranec Spes;Sabrina Hupp;F. Werner;F. Koch;K. Völker;Lisa Krebes;U. Kämmerer;K. Heinze;B. Braunger;M. Kuhn

C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness

• DOI: 10.1172/jci.insight.139910
• 发表时间: 2020-11-19
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Michel, Konstanze;Herwig, Melissa;Kuhn, Michaela
• 通讯作者: Kuhn, Michaela