Author + information
- Received September 23, 2015
- Revision received November 18, 2015
- Accepted November 23, 2015
- Published online February 23, 2016.
- Pankaj Arora, MDa,
- Connie Wu, PhDb,c,d,
- Tariq Hamid, PhDa,
- Garima Arora, MDa,
- Obiajulu Agha, BAc,
- Kaitlin Allen, BSc,
- Robert E.T. Tainsh, BAc,
- Dongjian Hu, BSb,e,
- Romy A. Ryan, BAb,
- Ibrahim J. Domian, MD, PhDb,f,
- Emmanuel S. Buys, PhDc,
- Donald B. Bloch, MDc,g,
- Sumanth D. Prabhu, MDa,
- Kenneth D. Bloch, MDb,c,
- Christopher Newton-Cheh, MD, MPHb,d,h and
- Thomas J. Wang, MDi,j,∗ ()
- aDivision of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- bCardiovascular Research Center, Department of Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts
- cAnesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts
- dProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- eDepartment of Biomedical Engineering, Boston University, Boston, Massachusetts
- fHarvard Stem Cell Institute, Cambridge, Massachusetts
- gDivision of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts
- hCenter for Human Genetic Research, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts
- iDivision of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee
- jVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University, Nashville, Tennessee
- ↵∗Reprint requests and correspondence:
Dr. Thomas J. Wang, Division of Cardiovascular Medicine, Vanderbilt University, 2220 Pierce Avenue, 383 PRB, Nashville, Tennessee 37232.
Background 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.
Objectives This study examined the effects of acute carbohydrate intake on the NP system in humans, and investigated underlying mechanisms.
Methods 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.
Results 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.
Conclusions 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.
This study was supported by the following grants: Harvard Catalyst 1 UL1 RR025758; R01-HL-086875; R01-HL-102780; R01-DK-082971; funds of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital; T32HL007208 from the National Heart, Lung, And Blood Institute; and the Leducq Foundation. Drs. Arora, Bloch, Newton-Cheh, and Wang are named as co-inventors on a patent application relating to the use of miRNAs for the treatment of hypertension and other disorders. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Arora and Wu contributed equally to this work.
- Received September 23, 2015.
- Revision received November 18, 2015.
- Accepted November 23, 2015.
- American College of Cardiology Foundation