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      Innovative Therapeutics : Designer Natriuretic Peptides

      , MD, PhD , , MD

      JACC: Basic to Translational Science

      Elsevier

      designer natriuretic peptide, drug development, heart failure, hypertension, natriuretic peptide, ANP, A-type natriuretic peptide, AS-BNP, alternatively spliced variant of BNP, BNP, B-type natriuretic peptide, BP, blood pressure, CD-NP, cenderitide, cGMP, cyclic guanosine monophosphate, CNP, C-type natriuretic peptide, CV, cardiovascular, DNP, D-type natriuretic peptide, FDA, Food and Drug Administration, GFR, glomerular filtration rate, HF, heart failure, HTN, hypertension, NEP, neprilysin, NP, natriuretic peptide, NPR, natriuretic peptide receptor, pGC, particulate guanylyl cyclase, RAAS, renin-angiotensin-aldosterone system, SQ, subcutaneous, URO, urodilatin, VNP, ventricular natriuretic peptide, ZD100, MANP

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          Summary

          Natriuretic peptides (NPs) are essential for the maintenance of volume homeostasis, and can be of myocardial, renal, and endothelial origin. Advances in peptide engineering have enabled the design of innovative designer NPs that go beyond native peptides in efficacy, specificity, and resistance to enzymatic degradation. Therefore, designer NPs provide an unparalleled opportunity for the treatment of cardiovascular disease. In this review, we report the conceptual framework of peptide engineering of the NPs that resulted in designer peptides for cardiovascular disease. We specifically provide an update on those currently in clinical trials for heart failure and hypertension.

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          Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.

          B-type natriuretic peptide is released from the cardiac ventricles in response to increased wall tension. We conducted a prospective study of 1586 patients who came to the emergency department with acute dyspnea and whose B-type natriuretic peptide was measured with a bedside assay. The clinical diagnosis of congestive heart failure was adjudicated by two independent cardiologists, who were blinded to the results of the B-type natriuretic peptide assay. The final diagnosis was dyspnea due to congestive heart failure in 744 patients (47 percent), dyspnea due to noncardiac causes in 72 patients with a history of left ventricular dysfunction (5 percent), and no finding of congestive heart failure in 770 patients (49 percent). B-type natriuretic peptide levels by themselves were more accurate than any historical or physical findings or laboratory values in identifying congestive heart failure as the cause of dyspnea. The diagnostic accuracy of B-type natriuretic peptide at a cutoff of 100 pg per milliliter was 83.4 percent. The negative predictive value of B-type natriuretic peptide at levels of less than 50 pg per milliliter was 96 percent. In multiple logistic-regression analysis, measurements of B-type natriuretic peptide added significant independent predictive power to other clinical variables in models predicting which patients had congestive heart failure. Used in conjunction with other clinical information, rapid measurement of B-type natriuretic peptide is useful in establishing or excluding the diagnosis of congestive heart failure in patients with acute dyspnea. Copyright 2002 Massachusetts Medical Society.
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            Natriuretic peptides.

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              Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes.

              The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of "brown adipocytes" within white fat depots. Activation of β-adrenergic receptors (β-ARs) can induce a functional "brown-like" adipocyte phenotype. As cardiac natriuretic peptides (NPs) and β-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPARγ coactivator-1α (PGC-1α) and UCP1 expression, induced mitochondriogenesis, and increased uncoupled and total respiration. At low concentrations, ANP and β-AR agonists additively enhanced expression of brown fat and mitochondrial markers in a p38 MAPK-dependent manner. Mice exposed to cold temperatures had increased levels of circulating NPs as well as higher expression of NP signaling receptor and lower expression of the NP clearance receptor (Nprc) in brown adipose tissue (BAT) and white adipose tissue (WAT). NPR-C(-/-) mice had markedly smaller WAT and BAT depots but higher expression of thermogenic genes such as Ucp1. Infusion of BNP into mice robustly increased Ucp1 and Pgc-1α expression in WAT and BAT, with corresponding elevation of respiration and energy expenditure. These results suggest that NPs promote "browning" of white adipocytes to increase energy expenditure, defining the heart as a central regulator of adipose tissue biology.
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                Author and article information

                Contributors
                Journal
                JACC Basic Transl Sci
                JACC Basic Transl Sci
                JACC: Basic to Translational Science
                Elsevier
                2452-302X
                26 December 2016
                December 2016
                26 December 2016
                : 1
                : 7
                : 557-567
                Affiliations
                Cardiorenal Research Laboratory, Department of Cardiovascular Diseases, College of Medicine, Mayo Clinic, Rochester, Minnesota
                Author notes
                [] Reprint requests and correspondence: Dr. Laura M.G. Meems, Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905. meems.laura@ 123456mayo.edu
                Article
                S2452-302X(16)30157-7
                10.1016/j.jacbts.2016.10.001
                5423722
                28497128
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                STATE-OF-THE-ART REVIEW

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