Inhibition of Atrial Natriuretic Peptide Clearance Reduces Myocardial Fibrosis and Improves Cardiac Function in Diabetic Rats

BackgroundNatriuretic peptides (NP) exert pleotropic effects through the recruitment of cGMP-signaling pathways depending on their bioavailability which is regulated by clearance receptors and peptidases. Here, we tested the hypothesis that increasing myocardial bioavailability of NP has a beneficial effect on heart failure. We studied the effects of a mutated NP, MANP, resistant to neprilysin in a model of diabetic cardiomyopathy characterized by a marked myocardial fibrosis. MethodsNatriuretic peptides as well as sacubritril were delivered via osmotic mini-pumps to high-fat/streptozotocin-induced type-2 diabetic (T2D) rats. Cardiac function was evaluated by echocardiography. Myocardial remodeling was studied by histological approaches, collagen phenotype and measurement of cGMP tissue concentration. Live-cell cGMP biosensing was conducted on cultured rat cardiac fibroblasts to investigate biological effects of NPs. cGMP signaling pathway was studied using various antibody arrays and biochemicals assays in cardiac tissue and cultured fibroblasts. ResultsMANP exhibits superior efficacy than ANP in reducing left ventricular dysfunction and to reduce myocardial fibrosis with less extracellular matrix deposition. In vitro, MANP and ANP similarly generated cGMP and activated PKG signaling pathway in cardiac fibroblasts, attenuating SMAD activation, collagen secretion and cell proliferation. Nevertheless, in vivo, MANP enhanced cardiac cGMP accumulation and was more potent than ANP in activating myocardial cGMP/PKG signaling and inhibiting the profibrotic SMAD pathway. Endopeptidase inhibition using sacubitril also led to cardiac cGMP accumulation and reduced myocardial fibrosis ConclusionsMyocardial bioavailability of ANP is a major determinant of peptide efficacy in reducing cardiac fibrosis and improving pump function during diabetic cardiomyopathy. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIMutated atrial natriuretic peptide (MANP) resistant to neprilysin degradation outperforms wild-type ANP in reducing myocardial fibrosis and improving cardiac function in type-2 diabetes (T2D) C_LIO_LIWhile the antifibrotic effect of the two ANP isoforms involves similarly cGMP-dependent PKG signaling and inhibition of fibroblast activation, MANP enhanced cGMP myocardial concentration more importantly than ANP. C_LIO_LISacubitril that inhibits ANP degradation also reduces cardiac fibrosis through myocardial accumulation of cGMP and activation of cGMP-dependent PKG signaling pathway. C_LIO_LICardiac bioavailability of natriuretic peptides is a major determinant of their effects on myocardial fibrosis and cardiac function. C_LI What Are the Clinical Implications?O_LIMyocardial bioavailability of natriuretic peptides is crucial for mitigating cardiac fibrosis and improving cardiac function in diabetic cardiomyopathy and heart failure in general. C_LIO_LIMANP holds the potential as a new treatment modality in the management of heart failure. C_LI