Cardiovascular Genetics: A News Round-Up Glucagon-Like Peptide-1 Receptor–Atrial Natriuretic Peptide Axis A Novel Mechanism for Blood Pressure Regulation Pankaj Arora, MD 1. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, Simpson JA, Drucker DJ. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19:567–575. 2. Newton-Cheh C, Larson MG, Vasan RS, Levy D, Bloch KD, Surti A, et al. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet. 2009;41:348–353. 3. Wang B, Zhong J, Lin H, Zhao Z, Yan Z, He H, et al. Blood pressurelowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab. 2013;15:737–749.
Study Hypothesis Population genetic studies have established the role of natriuretic peptide system in blood pressure (BP) regulation.2 The primary function of atrial natriuretic peptide (ANP) is to induce natriuresis through kidneys and promote vasodilatation in blood vessels. Clinical trials have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists reduce BP and decrease cardiovascular risk.3 In the current study, Kim et al1 uncover a novel link between GLP-1R and ANP, possibly elucidating the mechanism behind the reduction of BP that is observed with the use of GLP-1R agonists in clinical trials.
How Was the Hypothesis Tested? The authors1 used Glp1r−/− mice, Nppa−/− mice, and Rapgef4−/− mice (all on the C57BL/6 background) with the corresponding wild-type controls. Angiotensin II infusion and pressure overload secondary to transaortic constriction were used to induce hypertension in the mice. The authors tested whether liraglutide (GLP-1R agonist) infusion in the normotensive and hypertensive mice reduced BP, induced ANP secretion, and promoted aortic vasodilatation. Next, they determined the importance of ANP for the antihypertensive actions of liraglutide using ANP knockout (Nppa−/−) mice. Finally, the authors used Rapgef4−/− mice, which are deficient of the gene encoding the downstream effector, Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4), to determine the importance of Epac2 for the stimulatory effect of liraglutide on ANP secretion and its ability to lower BP.
reduce BP in the Glp1r−/− mice. Mice pretreated with natriuretic peptide receptor antagonist blocked the antihypertensive effects of liraglutide. Further, liraglutide did not directly increase cyclic GMP or relax preconstricted aortic rings. Liraglutide infusion increased urinary sodium excretion in normotensive and hypertensive wild-type mice, but there was neither a reduction in BP nor an increase in urinary sodium excretion in the Nppa−/− mice. These findings suggest an indirect ANP-dependent effect. Moreover, in both normotensive and hypertensive mice, the liraglutide-induced ANP secretion from cardiomyocytes was mediated by the activation of the downstream effector, Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4), because plasma ANP levels failed to increase in Rapgef4−/− mice after treatment with liraglutide. Expression of adenoviral Epac2 in atrial cardiomyocytes from hypertensive Rapgef4−/− mice restored the ability of liraglutide to induce ANP secretion from the cardiomyocytes. In addition, liraglutide significantly lowered both systolic and diastolic BP in hypertensive wild-type mice but had no effect on BP in hypertensive Rapgef4−/− mice. Taken together, these results suggest that liraglutide induces the release of ANP via a GLP-1R/Epac2 signaling pathway mechanism and regulates BP in a GLP-1R–ANP-dependent manner.
Implications This study uncovers a novel gut-heart axis by which a gut hormone, GLP-1, regulates ANP secretion from cardiomyocytes and lowers BP. One could speculate that these findings can be translated to treating hypertension in humans especially in patients with coexisting diabetes mellitus. Further research directed at pharmacologically augmenting the activation of natriuretic peptide system through GLP-1R pathway is warranted.
Acknowledgments Dr Arora is a member of the Early Career Committee of the American Heart Association Functional Genomics and Translational Biology Council.
Principal Findings GLP-1R expression was localized to atrial cardiomyocytes in both normotensive and hypertensive mice. Liraglutide produced a significant reduction in both systolic and diastolic BP in wild-type mice after angiotensin II infusion but did not
Disclosures None. Key Words: atrial natriuretic factor ◼ blood pressure ◼ glucagon-like peptide 1 ◼ natriuretic peptides
From the Early Career Committee of the American Heart Association, Functional Genomics & Translational Biology Council, Dallas, TX. Correspondence to Pankaj Arora, MD, Division of Cardiology, University of Alabama at Birmingham, 1808 7th Ave S, BDB 201, Birmingham, AL 35294. E-mail [email protected] (Circ Cardiovasc Genet. 2013;6:523.) © 2013 American Heart Association, Inc. Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org
DOI: 10.1161/CIRCGENETICS.113.000361
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Glucagon-Like Peptide-1 Receptor−Atrial Natriuretic Peptide Axis: A Novel Mechanism for Blood Pressure Regulation Pankaj Arora Circ Cardiovasc Genet. 2013;6:523 doi: 10.1161/CIRCGENETICS.113.000361 Circulation: Cardiovascular Genetics is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 1942-325X. Online ISSN: 1942-3268
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circgenetics.ahajournals.org/content/6/5/523
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Genetics can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Cardiovascular Genetics is online at: http://circgenetics.ahajournals.org//subscriptions/
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Study Hypothesis Population genetic studies have established the role of natriuretic peptide system in blood pressure (BP) regulation.2 The primary function of atrial natriuretic peptide (ANP) is to induce natriuresis through kidneys and promote vasodilatation in blood vessels. Clinical trials have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists reduce BP and decrease cardiovascular risk.3 In the current study, Kim et al1 uncover a novel link between GLP-1R and ANP, possibly elucidating the mechanism behind the reduction of BP that is observed with the use of GLP-1R agonists in clinical trials.
How Was the Hypothesis Tested? The authors1 used Glp1r−/− mice, Nppa−/− mice, and Rapgef4−/− mice (all on the C57BL/6 background) with the corresponding wild-type controls. Angiotensin II infusion and pressure overload secondary to transaortic constriction were used to induce hypertension in the mice. The authors tested whether liraglutide (GLP-1R agonist) infusion in the normotensive and hypertensive mice reduced BP, induced ANP secretion, and promoted aortic vasodilatation. Next, they determined the importance of ANP for the antihypertensive actions of liraglutide using ANP knockout (Nppa−/−) mice. Finally, the authors used Rapgef4−/− mice, which are deficient of the gene encoding the downstream effector, Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4), to determine the importance of Epac2 for the stimulatory effect of liraglutide on ANP secretion and its ability to lower BP.
reduce BP in the Glp1r−/− mice. Mice pretreated with natriuretic peptide receptor antagonist blocked the antihypertensive effects of liraglutide. Further, liraglutide did not directly increase cyclic GMP or relax preconstricted aortic rings. Liraglutide infusion increased urinary sodium excretion in normotensive and hypertensive wild-type mice, but there was neither a reduction in BP nor an increase in urinary sodium excretion in the Nppa−/− mice. These findings suggest an indirect ANP-dependent effect. Moreover, in both normotensive and hypertensive mice, the liraglutide-induced ANP secretion from cardiomyocytes was mediated by the activation of the downstream effector, Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4), because plasma ANP levels failed to increase in Rapgef4−/− mice after treatment with liraglutide. Expression of adenoviral Epac2 in atrial cardiomyocytes from hypertensive Rapgef4−/− mice restored the ability of liraglutide to induce ANP secretion from the cardiomyocytes. In addition, liraglutide significantly lowered both systolic and diastolic BP in hypertensive wild-type mice but had no effect on BP in hypertensive Rapgef4−/− mice. Taken together, these results suggest that liraglutide induces the release of ANP via a GLP-1R/Epac2 signaling pathway mechanism and regulates BP in a GLP-1R–ANP-dependent manner.
Implications This study uncovers a novel gut-heart axis by which a gut hormone, GLP-1, regulates ANP secretion from cardiomyocytes and lowers BP. One could speculate that these findings can be translated to treating hypertension in humans especially in patients with coexisting diabetes mellitus. Further research directed at pharmacologically augmenting the activation of natriuretic peptide system through GLP-1R pathway is warranted.
Acknowledgments Dr Arora is a member of the Early Career Committee of the American Heart Association Functional Genomics and Translational Biology Council.
Principal Findings GLP-1R expression was localized to atrial cardiomyocytes in both normotensive and hypertensive mice. Liraglutide produced a significant reduction in both systolic and diastolic BP in wild-type mice after angiotensin II infusion but did not
Disclosures None. Key Words: atrial natriuretic factor ◼ blood pressure ◼ glucagon-like peptide 1 ◼ natriuretic peptides
From the Early Career Committee of the American Heart Association, Functional Genomics & Translational Biology Council, Dallas, TX. Correspondence to Pankaj Arora, MD, Division of Cardiology, University of Alabama at Birmingham, 1808 7th Ave S, BDB 201, Birmingham, AL 35294. E-mail [email protected] (Circ Cardiovasc Genet. 2013;6:523.) © 2013 American Heart Association, Inc. Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org
DOI: 10.1161/CIRCGENETICS.113.000361
Downloaded from http://circgenetics.ahajournals.org/ 523 at Thomas Jefferson Universi on March 10, 2015
Glucagon-Like Peptide-1 Receptor−Atrial Natriuretic Peptide Axis: A Novel Mechanism for Blood Pressure Regulation Pankaj Arora Circ Cardiovasc Genet. 2013;6:523 doi: 10.1161/CIRCGENETICS.113.000361 Circulation: Cardiovascular Genetics is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 1942-325X. Online ISSN: 1942-3268
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circgenetics.ahajournals.org/content/6/5/523
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Genetics can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Cardiovascular Genetics is online at: http://circgenetics.ahajournals.org//subscriptions/
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