Cardiomyocyte-derived C-type natriuretic peptide diminishes myocardial ischaemic injury by promoting revascularisation and limiting fibrotic burden

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research Pub Date : 2024-10-05 DOI:10.1016/j.phrs.2024.107447

Vanessa J. Lowe , Aisah A. Aubdool , Amie J. Moyes , Joshua P. Dignam , C. Perez-Ternero , Reshma S. Baliga , Nicola Smart , Adrian J. Hobbs

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引用次数: 0

Abstract

Background

C-type natriuretic peptide (CNP) is a significant player in the maintenance of cardiac and vascular homeostasis regulating local blood flow, platelet and leukocyte activation, heart structure and function, angiogenesis and metabolic balance. Since such processes are perturbed in myocardial infarction (MI), we explored the role of cardiomyocyte-derived CNP, and pharmacological administration of the peptide, in offsetting the pathological consequences of MI.

Methods

Wild type (WT) and cardiomyocyte-restricted CNP null (cmCNP^-/-) mice were subjected to left anterior descending coronary artery (LADCA) ligation and acute effects on infarct size and longer-term outcomes of cardiac repair explored. Heart structure and function were assessed by combined echocardiographic and molecular analyses. Pharmacological administration of CNP (0.2 mg/kg/day; s.c.) was utilized to assess therapeutic potential.

Results

Compared to WT littermates, cmCNP^-/- mice had a modestly increased infarct size following LADCA ligation but without significant deterioration of cardiac structural and functional indices. However, cmCNP^-/- animals exhibited overtly worse heart morphology and contractility 6 weeks following MI, with particularly deleterious reductions in left ventricular ejection fraction, dilatation, fibrosis and revascularization. This phenotype was largely recapitulated in animals with global deletion of natriuretic peptide receptor (NPR)-C (NPR-C^-/-). Pharmacological administration of CNP rescued the deleterious pathology in WT and cmCNP^-/-, but not NPR-C^-/-, animals.

Conclusions and implications

Cardiomyocytes synthesize and release CNP as an intrinsic protective mechanism in response to MI that reduces cardiac structural and functional deficits; these salutary actions are primarily NPR-C-dependent. Pharmacological targeting of CNP may represent a new therapeutic option for MI.

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心肌细胞源性 C 型钠尿肽可通过促进血管再通和限制纤维化负担来减轻心肌缺血损伤。

背景：C型钠尿肽（CNP）在维持心脏和血管稳态方面发挥着重要作用，可调节局部血流、血小板和白细胞活化、心脏结构和功能、血管生成和代谢平衡。由于心肌梗死（MI）时这些过程会受到干扰，我们探讨了心肌细胞衍生的 CNP 和药理施用该肽在抵消心肌梗死病理后果中的作用：方法：对野生型（WT）和心肌细胞限制性 CNP 空位（cmCNP-/-）小鼠进行冠状动脉左前降支（LADCA）结扎，并探讨其对梗死面积的急性影响和心脏修复的长期效果。心脏结构和功能通过超声心动图和分子分析进行综合评估。利用药理学方法给予 CNP（0.2 毫克/千克/天；静脉注射）来评估治疗潜力：结果：与WT同窝鼠相比，cmCNP-/-小鼠在结扎LADCA后梗死面积略有增加，但心脏结构和功能指标没有明显恶化。然而，cmCNP-/-动物在心肌梗死后6周表现出明显恶化的心脏形态和收缩力，尤其是左心室射血分数、扩张、纤维化和血管再通的有害减少。这种表型在全面缺失钠尿肽受体（NPR）-C（NPR-C-/-）的动物中基本重现。在 WT 和 cmCNP-/- 而非 NPR-C-/- 动物中，药理施用 CNP 可挽救有害病理：心肌细胞合成和释放 CNP 是对心肌缺血的内在保护机制，可减轻心脏结构和功能障碍；这些有益作用主要依赖于 NPR-C。以 CNP 为药理靶点可能是治疗心肌缺血的一种新方法。

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来源期刊

Pharmacological research 医学-药学

CiteScore

18.70

自引率

3.20%

发文量

491

审稿时长

8 days

期刊介绍： Pharmacological Research publishes cutting-edge articles in biomedical sciences to cover a broad range of topics that move the pharmacological field forward. Pharmacological research publishes articles on molecular, biochemical, translational, and clinical research (including clinical trials); it is proud of its rapid publication of accepted papers that comprises a dedicated, fast acceptance and publication track for high profile articles.