Acute Metabolic Influences on the Natriuretic Peptide System in Humans

• Published in: Journal of the American College of Cardiology Vol. 67; no. 7; pp. 804 - 812
• Main Authors: Arora, Pankaj, Wu, Connie, Hamid, Tariq, Arora, Garima, Agha, Obiajulu, Allen, Kaitlin, Tainsh, Robert E.T., Hu, Dongjian, Ryan, Romy A., Domian, Ibrahim J., Buys, Emmanuel S., Bloch, Donald B., Prabhu, Sumanth D., Bloch, Kenneth D., Newton-Cheh, Christopher, Wang, Thomas J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.02.2016; Elsevier Limited
• Subjects: Adult; Animals; Atrial Natriuretic Factor - biosynthesis; Atrial Natriuretic Factor - genetics; Blood Pressure - physiology; Body mass index; Carbohydrates; Cardiology; cardiomyocyte; Cardiomyocytes; Cardiovascular; Female; Gene Expression Regulation; glucose; Heart; Hep G2 Cells - metabolism; Humans; Insulin; Insulin resistance; Male; Metabolism; Mice; micro ribonucleic acid; MicroRNAs - biosynthesis; MicroRNAs - genetics; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Natriuretic Peptide, Brain - biosynthesis; Natriuretic Peptide, Brain - genetics; Natriuretic Peptides - biosynthesis; Natriuretic Peptides - genetics; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Peptide Fragments - biosynthesis; Peptide Fragments - genetics; Peptides; Protein Precursors; RNA, Messenger - genetics; Rodents; Signal Transduction; Sodium - metabolism; Stem cells; Studies; micro ribonucleic acid; glucose; NP; ANP; BNP; 3′UTR; mRNA; BP; pri-miR-425; NT-proANP; NF-κB; miRNA-425; NT-proBNP; cardiomyocyte; miRNA; pri-miRNA; hESC-CM; obesity; BMI; nuclear factor kappa B; primary transcript of miR-425; N-terminal pro-atrial natriuretic peptide; messenger ribonucleic acid; atrial natriuretic peptide; base pair(s); 3′ untranslated region; blood pressure; micro ribonucleic acid 425; body mass index; natriuretic peptide; primary transcript of micro ribonucleic acid; B-type natriuretic peptide; human embryonic stem cell–derived cardiomyocyte; N-terminal pro–B-type natriuretic peptide
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2015.11.049

The cardiac natriuretic peptides (NPs), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), have central roles in sodium and blood pressure regulation. Extracardiac factors (e.g., obesity and diabetes) influence NP production, potentially altering cardiovascular responses to volume and pressure stress. This study examined the effects of acute carbohydrate intake on the NP system in humans, and investigated underlying mechanisms. Normotensive subjects (N = 33) were given a high-carbohydrate shake. Venous blood was sampled to measure N-terminal (NT)-proANP and NT-proBNP levels. Human embryonic stem cell–derived cardiomyocytes (hESC-CMs) and HepG2 cells were treated with glucose, and expression levels of NPs and micro ribonucleic acid 425 (miR-425), a negative regulator of ANP, were examined. The role of nuclear factor kappa B (NF-κB) in the glucose-mediated effects was investigated using a NF-κB inhibitor and expression plasmids encoding NF-κB subunits. We observed a 27% reduction in the levels of circulating NT-proANP (p < 0.001, maximal at 6 h) after carbohydrate challenge, with no effect on NT-proBNP levels in our human subjects. Glucose treatment of hESC-CMs for 6 h and 24 h increased levels of the primary transcript of miR-425 (pri-miR-425) and mature miR-425. A corresponding decrease in NPPA messenger RNA levels was also observed at both time points. Overexpression of NF-κB subunits in H9c2 cardiomyocytes increased miR-425 levels, whereas inhibition of NF-κB abrogated the glucose-mediated increase in pri-miR-425 levels in HepG2 cells. Acute carbohydrate challenge is associated with a reduction in ANP production. The mechanism appears to involve a glucose-induced increase in the expression of miR-425, mediated by NF-κB signaling.