Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy.

Background: Dilated cardiomyopathy (DCM), a specific form of cardiomyopathy, frequently presents clinically with either left ventricular or biventricular enlargement, often leading to progressive heart failure. In recent years, the application of bioinformatics technology to scrutinize the onset, progression, and prognosis of DCM has emerged as a fervent area of interest among scholars globally. Methods: In this study, core genes closely related to DCM were identified through bioinformatics analysis, including weighted gene co expression network analysis (WGCNA) and single sample gene set enrichment analysis (ssGSEA) and so on. The correlation was verified through experiments on DCM patients, DCM rat models, and core gene knockout mice. Subsequently, the effects of glucocorticoids on DCM and the regulation of core genes were observed. Result: In the present study, natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through WGCNA and ssGSEA. Significant impairment of cardiac and renal function was observed in both DCM patients and rats, concomitant with a notable reduction in NPR1 expression. NPR1 KO mice displayed symptomatic manifestations of DCM, underscoring the pivotal role of NPR1 in its pathogenesis. Notably, glucocorticoid treatment led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression. Discussion: These findings highlight the critical involvement of NPR1 in the pathophysiology of DCM and its potential as a key target for glucocorticoid-based DCM therapy. The study provides a robust theoretical and experimental foundation for further investigations into DCM etiology and therapeutic strategies.

Glucocorticoids ameliorate cardiorenal syndrome through the NPR1/SGK1 pathway in natriuretic peptide receptor A­heterozygous mice.

Natriuretic peptides, which are produced by the heart, bind to natriuretic peptide receptor A (NPR1 encoded by natriuretic peptide receptor 1 gene) and cause vasodilation and natriuresis. Thus, they serve an important role in regulating blood pressure. In the present study, microinjection of CRISPR associated protein 9/single guide RNA into fertilized C57BL/6N mouse eggs was performed to generate filial generation zero (F0) Npr1 knockout homozygous mice (Npr1-/-). F0 mice mated with wild-type (WT) mice to obtain F1 Npr1 knockout heterozygous mice with stable heredity (Npr1+/-). F1 self-hybridization was used to expand the population of heterozygous mice (Npr1+/-). The present study performed echocardiography to investigate the impact of NPR1 gene knockdown on cardiac function. Compared with those in the WT group (C57BL/6N male mice), the left ventricular ejection fraction, myocardial contractility and renal sodium and potassium excretion and creatinine-clearance rates were decreased, indicating that Npr1 knockdown induced cardiac and renal dysfunction. In addition, expression of serum glucocorticoid-regulated kinase 1 (SGK1) increased significantly compared with that in WT mice. However, glucocorticoids (dexamethasone) upregulated NPR1 and inhibited SGK1 and alleviated cardiac and renal dysfunction caused by Npr1 gene heterozygosity. SGK1 inhibitor GSK650394 ameliorate cardiorenal syndrome by suppressing SGK1. Briefly, glucocorticoids inhibited SGK1 by upregulating NPR1, thereby ameliorating cardiorenal impairment caused by Npr1 gene heterozygosity. The present findings provided novel insight into the understanding of cardiorenal syndrome and suggested that glucocorticoids targeting the NPR1/SGK1 pathway may be a potential therapeutic target to treat cardiorenal syndrome.