Role of PDE5/cGMP/cGMP-dependent Protein Kinase in Cardiac Hypertrophy and Remodeling

PDE5/cGMP/cGMP依赖性蛋白激酶在心脏肥大和重构中的作用

• 批准号: 50233464
• 负责人: Professor Dr. Robert Lukowski
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/50233464?language=en
• 关键词: Role; PDE5; cGMP; dependent; Protein

Cardiac hypertrophy is effectively decreased by natriuretic peptides, particulate guanylyl cyclase A and cyclic guanosine monophosphate (cGMP). The available evidence including inhibition of phosphodiesterase 5 (PDE5) by sildenafil suggests that cGMP signals through cGMP kinase I (cGKI). So far, mice that carry a global or cardiomyocyte-specific deletion of cGKI showed no cardiac hypertrophy. These discrepant results may be explained either by the use of inadequate mouse models caused by a) multiple interfering diseases observed in the conventional cGKI knockouts or b) by deletion of cGKI in the wrong cells or c) a cGKI-independent signaling cascade for cGMP. For example, it is possible that cardiac fibroblast contribute to the antihypertrophic effects of atrial natriuretic peptide (ANP), because in normal animals we can detect PDE5 only in the latter cells. The focus of the proposed research will be the use of new and better mouse models to study the contribution of cGKl and PDE5/cGMP to cardiac hypertrophy.

利钠肽、颗粒鸟苷酸环化酶 A 和环磷酸鸟苷 (cGMP) 可有效减少心脏肥大。包括西地那非抑制磷酸二酯酶 5 (PDE5) 在内的现有证据表明，cGMP 信号通过 cGMP 激酶 I (cGKI) 进行。到目前为止，携带 cGKI 整体或心肌细胞特异性缺失的小鼠没有表现出心脏肥大。这些不一致的结果可能是由于使用了不适当的小鼠模型引起的，原因是：a）在传统的 cGKI 敲除中观察到的多种干扰疾病，或 b）在错误的细胞中删除了 cGKI，或 c）cGKI 独立的 cGMP 信号级联。例如，心脏成纤维细胞可能有助于心房钠尿肽 (ANP) 的抗肥厚作用，因为在正常动物中，我们只能在后者细胞中检测到 PDE5。拟议研究的重点将是使用新的、更好的小鼠模型来研究cGK1和PDE5/cGMP对心脏肥大的贡献。