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1.
J Am Heart Assoc ; 6(2)2017 02 10.
Article in English | MEDLINE | ID: mdl-28188250

ABSTRACT

BACKGROUND: Recent studies have shown that plasma levels of the biologically inactive prohormone for brain natriuretic peptide (proBNP) are increased in patients with heart failure. This can contribute to a reduction in the effectiveness of circulating BNP and exacerbate heart failure progression. The precise mechanisms governing the increase in proBNP remain unclear, however. METHODS AND RESULTS: We used our recently developed, highly sensitive human proBNP assay system to investigate the mechanisms underlying the increase in plasma proBNP levels. We divided 53 consecutive patients hospitalized with heart failure into 2 groups based on their aortic plasma levels of immunoreactive BNP. Patients with higher levels exhibited more severe heart failure, a higher proportion of proBNP among the immunoreactive BNP forms secreted from failing hearts, and a weaker effect of BNP as estimated from the ratio of plasma cyclic guanosine monophosphate levels to log-transformed plasma BNP levels. Glycosylation at threonines 48 and 71 of human proBNP contributed to the increased secretion of proBNP by attenuating its processing, and GalNAc-transferase (GALNT) 1 and 2 mediated the glycosylation-regulated increase in cardiac human proBNP secretion. Cardiac GALNT1 and 2 expression was suppressed by microRNA (miR)-30, which is abundantly expressed in the myocardium of healthy hearts, but is suppressed in failing hearts. CONCLUSIONS: We have elucidated a novel miR-30-GALNT1/2 axis whose dysregulation increases the proportion of inactive proBNP secreted by the heart and impairs the compensatory actions of BNP during the progression of heart failure.


Subject(s)
Aorta, Thoracic/metabolism , Gene Expression Regulation , Heart Failure/genetics , MicroRNAs/genetics , Myocardium/metabolism , N-Acetylgalactosaminyltransferases/genetics , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Aged , Animals , Animals, Newborn , Biomarkers/blood , Blotting, Western , Cells, Cultured , Chromatography, Gel , Disease Models, Animal , Disease Progression , Echocardiography , Female , Follow-Up Studies , Glycosylation , Heart Failure/diagnosis , Heart Failure/metabolism , Heart Ventricles/diagnostic imaging , Heart Ventricles/metabolism , Heart Ventricles/physiopathology , Humans , Male , MicroRNAs/biosynthesis , Middle Aged , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , N-Acetylgalactosaminyltransferases/biosynthesis , Protein Precursors , Rats , Rats, Inbred Dahl , Real-Time Polymerase Chain Reaction , Retrospective Studies , Signal Transduction , Polypeptide N-acetylgalactosaminyltransferase
2.
Am J Physiol Regul Integr Comp Physiol ; 309(6): R639-49, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26136529

ABSTRACT

We investigated the molecular mechanism underlying the processing of pro-B-type natriuretic peptide (proBNP). Rat neonatal atrial and ventricular myocytes were cultured separately. We examined the molecular forms of secreted and intracellular BNP in atrial and ventricular myocytes; levels of corin and furin mRNA in atrial and ventricular myocytes; the effect their knockdown on proBNP processing; plasma molecular forms of BNP from rats and humans with and without heart failure; and the impact of the distance between the glycosylation and cleavage sites in wild-type and mutant human proBNP, expressed in rat myocytes transfected with lentiviral vectors. BNP was the major molecular form secreted by atrial and ventricular myocytes. Transfection of furin siRNA reduced proBNP processing in both atrial and ventricular myocytes; however, transfection of corin siRNA did not reduce it. BNP was the major molecular form in rat plasma, whereas proBNP was the major form in human plasma. The relative fraction of human BNP in rat myocytes expressing human proBNP was about 60%, but increasing the distance between the glycosylation and cleavage sites through mutation, increased the processed fraction correspondingly. These results suggest that proBNP is processed into BNP intracellularly by furin. The level of proBNP processing is lower in humans than rats, most likely due to the smaller distance between the O-glycosylation and cleavage sites in humans.


Subject(s)
Natriuretic Peptide, Brain/metabolism , Peptide Fragments/metabolism , Aged , Animals , Atrial Natriuretic Factor/metabolism , Cells, Cultured , Culture Media, Conditioned , Female , Furin/metabolism , Glycosylation , Heart Atria/cytology , Heart Atria/metabolism , Heart Failure/metabolism , Heart Ventricles/cytology , Heart Ventricles/metabolism , Humans , Male , Middle Aged , Muscle Cells/metabolism , Natriuretic Peptide, Brain/genetics , Peptide Fragments/genetics , Rats , Rats, Inbred Dahl , Serine Endopeptidases/metabolism , Species Specificity
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