Saxagliptin and tadalafil differentially alter cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine

Jessica A. Hiemstra, Dong I. Lee, Khalid Chakir, Manuel Gutiérrez-Aguilar, Kurt D. Marshall, Pamela J. Zgoda, Noelany Cruz Rivera, Daniel G. Dozier, Brian S. Ferguson, Denise M. Heublein, John C Jr. Burnett, Carolin Scherf, Jan R. Ivey, Gianmaria Minervini, Kerry S. McDonald, Christopher P. Baines, Maike Krenz, Timothy L. Domeier, Craig A. Emter

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background-Cyclic guanosine monophosphate-protein kinase G-phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl-peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function. Methods and Results-We assessed LV hypertrophy and function at the organ and cellular level in aortic-banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end-systolic pressure-volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil-treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening-frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium-retention capacity and Complex II-dependent respiratory control, was present in both HF and tadalafil-treated animals. Conclusions-Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

Original languageEnglish (US)
Article numbere003277
JournalJournal of the American Heart Association
Volume5
Issue number4
DOIs
StatePublished - 2016

Fingerprint

Cyclic GMP
Left Ventricular Function
Swine
Heart Failure
Type 5 Cyclic Nucleotide Phosphodiesterases
Neuropeptide Y
Collagen
Guanylate Kinases
Dipeptidyl-Peptidase IV Inhibitors
Phosphodiesterase 5 Inhibitors
Cyclic GMP-Dependent Protein Kinases
Left Ventricular Hypertrophy
Tadalafil
saxagliptin
Mechanics
Cardiac Myocytes
Hypertrophy
Blood Pressure
Calcium
Pharmaceutical Preparations

Keywords

  • cGMP-PKG-PDE5
  • Heart failure with preserved ejection fraction
  • Pressure-overload
  • Saxagliptin
  • Tadalafil

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Saxagliptin and tadalafil differentially alter cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine. / Hiemstra, Jessica A.; Lee, Dong I.; Chakir, Khalid; Gutiérrez-Aguilar, Manuel; Marshall, Kurt D.; Zgoda, Pamela J.; Rivera, Noelany Cruz; Dozier, Daniel G.; Ferguson, Brian S.; Heublein, Denise M.; Burnett, John C Jr.; Scherf, Carolin; Ivey, Jan R.; Minervini, Gianmaria; McDonald, Kerry S.; Baines, Christopher P.; Krenz, Maike; Domeier, Timothy L.; Emter, Craig A.

In: Journal of the American Heart Association, Vol. 5, No. 4, e003277, 2016.

Research output: Contribution to journalArticle

Hiemstra, JA, Lee, DI, Chakir, K, Gutiérrez-Aguilar, M, Marshall, KD, Zgoda, PJ, Rivera, NC, Dozier, DG, Ferguson, BS, Heublein, DM, Burnett, JCJ, Scherf, C, Ivey, JR, Minervini, G, McDonald, KS, Baines, CP, Krenz, M, Domeier, TL & Emter, CA 2016, 'Saxagliptin and tadalafil differentially alter cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine', Journal of the American Heart Association, vol. 5, no. 4, e003277. https://doi.org/10.1161/JAHA.116.003277
Hiemstra, Jessica A. ; Lee, Dong I. ; Chakir, Khalid ; Gutiérrez-Aguilar, Manuel ; Marshall, Kurt D. ; Zgoda, Pamela J. ; Rivera, Noelany Cruz ; Dozier, Daniel G. ; Ferguson, Brian S. ; Heublein, Denise M. ; Burnett, John C Jr. ; Scherf, Carolin ; Ivey, Jan R. ; Minervini, Gianmaria ; McDonald, Kerry S. ; Baines, Christopher P. ; Krenz, Maike ; Domeier, Timothy L. ; Emter, Craig A. / Saxagliptin and tadalafil differentially alter cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine. In: Journal of the American Heart Association. 2016 ; Vol. 5, No. 4.
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abstract = "Background-Cyclic guanosine monophosphate-protein kinase G-phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl-peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function. Methods and Results-We assessed LV hypertrophy and function at the organ and cellular level in aortic-banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end-systolic pressure-volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil-treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening-frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium-retention capacity and Complex II-dependent respiratory control, was present in both HF and tadalafil-treated animals. Conclusions-Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.",
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author = "Hiemstra, {Jessica A.} and Lee, {Dong I.} and Khalid Chakir and Manuel Guti{\'e}rrez-Aguilar and Marshall, {Kurt D.} and Zgoda, {Pamela J.} and Rivera, {Noelany Cruz} and Dozier, {Daniel G.} and Ferguson, {Brian S.} and Heublein, {Denise M.} and Burnett, {John C Jr.} and Carolin Scherf and Ivey, {Jan R.} and Gianmaria Minervini and McDonald, {Kerry S.} and Baines, {Christopher P.} and Maike Krenz and Domeier, {Timothy L.} and Emter, {Craig A.}",
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T1 - Saxagliptin and tadalafil differentially alter cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine

AU - Hiemstra, Jessica A.

AU - Lee, Dong I.

AU - Chakir, Khalid

AU - Gutiérrez-Aguilar, Manuel

AU - Marshall, Kurt D.

AU - Zgoda, Pamela J.

AU - Rivera, Noelany Cruz

AU - Dozier, Daniel G.

AU - Ferguson, Brian S.

AU - Heublein, Denise M.

AU - Burnett, John C Jr.

AU - Scherf, Carolin

AU - Ivey, Jan R.

AU - Minervini, Gianmaria

AU - McDonald, Kerry S.

AU - Baines, Christopher P.

AU - Krenz, Maike

AU - Domeier, Timothy L.

AU - Emter, Craig A.

PY - 2016

Y1 - 2016

N2 - Background-Cyclic guanosine monophosphate-protein kinase G-phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl-peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function. Methods and Results-We assessed LV hypertrophy and function at the organ and cellular level in aortic-banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end-systolic pressure-volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil-treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening-frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium-retention capacity and Complex II-dependent respiratory control, was present in both HF and tadalafil-treated animals. Conclusions-Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

AB - Background-Cyclic guanosine monophosphate-protein kinase G-phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl-peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function. Methods and Results-We assessed LV hypertrophy and function at the organ and cellular level in aortic-banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end-systolic pressure-volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil-treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening-frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium-retention capacity and Complex II-dependent respiratory control, was present in both HF and tadalafil-treated animals. Conclusions-Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

KW - cGMP-PKG-PDE5

KW - Heart failure with preserved ejection fraction

KW - Pressure-overload

KW - Saxagliptin

KW - Tadalafil

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