The dipeptidyl peptidase-4 inhibitor-sitagliptin modulates calcium dysregulation, inflammation, and PPARs in hypertensive cardiomyocytes

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Abstract

Background Hypertension induces cardiac dysfunction, calcium (Ca 2 +) dysregulation, and arrhythmogenesis. Dipeptidyl peptidase (DPP)-4 inhibitors, an antidiabetic agent with anti-inflammation and anti-hypertension potential, may regulate peroxisome proliferator-activated receptors (PPARs)-α, -γ, and -δ and Ca2 + homeostasis. Objective The purpose of this study was to investigate whether DPP-4 inhibitor, sitagliptin, can modulate PPARs and Ca2 + handling proteins in hypertensive hearts. Methods A Western blot analysis was used to evaluate protein expressions of myocardial PPAR isoforms, tumor necrosis factor (TNF)-α, interleukin (IL)-6, sarcoplasmic reticulum ATPase (SERCA2a), Na+-Ca2 + exchanger (NCX), ryanodine receptor (RyR), voltage-dependent Ca2 + (CaV1.2), slow-voltage potassium currents (Kvs), angiotensin II type 1 receptor (AT1R), and receptor of advanced glycated end-products (RAGE) from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and SHR treated with sitagliptin (10 mg/kg for 4 weeks). Conventional microelectrodes were used to record action potentials (APs) in the ventricular myocytes from each group. Results Compared to the control group, SHR had lower cardiac PPAR-α and PPAR-δ protein expressions, but had greater cardiac PPAR-γ levels, and TNF-α, IL-6, RAGE, and AT1R protein expressions, which were ameliorated in the sitagliptin-treated SHR. SHR had prolonged QT interval and AP duration with less SERCA2a and RyR, and greater CaV1.2 expressions, which were also attenuated in sitagliptin-treated SHR. Conclusions Sitagliptin significantly changed the cardiac electrophysiological characteristics and Ca2 + regulation, which may have been caused by its effects on cardiac PPARs, proinflammatory cytokines, and AT1R.

Original languageEnglish
Pages (from-to)5390-5395
Number of pages6
JournalInternational Journal of Cardiology
Volume168
Issue number6
DOIs
Publication statusPublished - Oct 15 2013

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Dipeptidyl-Peptidase IV Inhibitors
Peroxisome Proliferator-Activated Receptors
Cardiac Myocytes
Inbred SHR Rats
Inflammation
Calcium
Angiotensin Type 1 Receptor
Ryanodine Receptor Calcium Release Channel
Action Potentials
Proteins
Tumor Necrosis Factor-alpha
Hypertension
Interleukin-6 Receptors
Inbred WKY Rats
Sarcoplasmic Reticulum
Microelectrodes
Sitagliptin Phosphate
Hypoglycemic Agents
Muscle Cells
Interleukin-6

Keywords

  • Calcium handling
  • Cardiomyocytes
  • DPP-4 inhibitor
  • Hypertension
  • Sitagliptin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{b99ef1daf5654fb798be95951de3ff71,
title = "The dipeptidyl peptidase-4 inhibitor-sitagliptin modulates calcium dysregulation, inflammation, and PPARs in hypertensive cardiomyocytes",
abstract = "Background Hypertension induces cardiac dysfunction, calcium (Ca 2 +) dysregulation, and arrhythmogenesis. Dipeptidyl peptidase (DPP)-4 inhibitors, an antidiabetic agent with anti-inflammation and anti-hypertension potential, may regulate peroxisome proliferator-activated receptors (PPARs)-α, -γ, and -δ and Ca2 + homeostasis. Objective The purpose of this study was to investigate whether DPP-4 inhibitor, sitagliptin, can modulate PPARs and Ca2 + handling proteins in hypertensive hearts. Methods A Western blot analysis was used to evaluate protein expressions of myocardial PPAR isoforms, tumor necrosis factor (TNF)-α, interleukin (IL)-6, sarcoplasmic reticulum ATPase (SERCA2a), Na+-Ca2 + exchanger (NCX), ryanodine receptor (RyR), voltage-dependent Ca2 + (CaV1.2), slow-voltage potassium currents (Kvs), angiotensin II type 1 receptor (AT1R), and receptor of advanced glycated end-products (RAGE) from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and SHR treated with sitagliptin (10 mg/kg for 4 weeks). Conventional microelectrodes were used to record action potentials (APs) in the ventricular myocytes from each group. Results Compared to the control group, SHR had lower cardiac PPAR-α and PPAR-δ protein expressions, but had greater cardiac PPAR-γ levels, and TNF-α, IL-6, RAGE, and AT1R protein expressions, which were ameliorated in the sitagliptin-treated SHR. SHR had prolonged QT interval and AP duration with less SERCA2a and RyR, and greater CaV1.2 expressions, which were also attenuated in sitagliptin-treated SHR. Conclusions Sitagliptin significantly changed the cardiac electrophysiological characteristics and Ca2 + regulation, which may have been caused by its effects on cardiac PPARs, proinflammatory cytokines, and AT1R.",
keywords = "Calcium handling, Cardiomyocytes, DPP-4 inhibitor, Hypertension, Sitagliptin",
author = "Lee, {T. I.} and Kao, {Y. H.} and Chen, {Y. C.} and Huang, {J. H.} and Hsu, {M. I.} and Chen, {Y. J.}",
year = "2013",
month = "10",
day = "15",
doi = "10.1016/j.ijcard.2013.08.051",
language = "English",
volume = "168",
pages = "5390--5395",
journal = "International Journal of Cardiology",
issn = "0167-5273",
publisher = "Elsevier Ireland Ltd",
number = "6",

}

TY - JOUR

T1 - The dipeptidyl peptidase-4 inhibitor-sitagliptin modulates calcium dysregulation, inflammation, and PPARs in hypertensive cardiomyocytes

AU - Lee, T. I.

AU - Kao, Y. H.

AU - Chen, Y. C.

AU - Huang, J. H.

AU - Hsu, M. I.

AU - Chen, Y. J.

PY - 2013/10/15

Y1 - 2013/10/15

N2 - Background Hypertension induces cardiac dysfunction, calcium (Ca 2 +) dysregulation, and arrhythmogenesis. Dipeptidyl peptidase (DPP)-4 inhibitors, an antidiabetic agent with anti-inflammation and anti-hypertension potential, may regulate peroxisome proliferator-activated receptors (PPARs)-α, -γ, and -δ and Ca2 + homeostasis. Objective The purpose of this study was to investigate whether DPP-4 inhibitor, sitagliptin, can modulate PPARs and Ca2 + handling proteins in hypertensive hearts. Methods A Western blot analysis was used to evaluate protein expressions of myocardial PPAR isoforms, tumor necrosis factor (TNF)-α, interleukin (IL)-6, sarcoplasmic reticulum ATPase (SERCA2a), Na+-Ca2 + exchanger (NCX), ryanodine receptor (RyR), voltage-dependent Ca2 + (CaV1.2), slow-voltage potassium currents (Kvs), angiotensin II type 1 receptor (AT1R), and receptor of advanced glycated end-products (RAGE) from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and SHR treated with sitagliptin (10 mg/kg for 4 weeks). Conventional microelectrodes were used to record action potentials (APs) in the ventricular myocytes from each group. Results Compared to the control group, SHR had lower cardiac PPAR-α and PPAR-δ protein expressions, but had greater cardiac PPAR-γ levels, and TNF-α, IL-6, RAGE, and AT1R protein expressions, which were ameliorated in the sitagliptin-treated SHR. SHR had prolonged QT interval and AP duration with less SERCA2a and RyR, and greater CaV1.2 expressions, which were also attenuated in sitagliptin-treated SHR. Conclusions Sitagliptin significantly changed the cardiac electrophysiological characteristics and Ca2 + regulation, which may have been caused by its effects on cardiac PPARs, proinflammatory cytokines, and AT1R.

AB - Background Hypertension induces cardiac dysfunction, calcium (Ca 2 +) dysregulation, and arrhythmogenesis. Dipeptidyl peptidase (DPP)-4 inhibitors, an antidiabetic agent with anti-inflammation and anti-hypertension potential, may regulate peroxisome proliferator-activated receptors (PPARs)-α, -γ, and -δ and Ca2 + homeostasis. Objective The purpose of this study was to investigate whether DPP-4 inhibitor, sitagliptin, can modulate PPARs and Ca2 + handling proteins in hypertensive hearts. Methods A Western blot analysis was used to evaluate protein expressions of myocardial PPAR isoforms, tumor necrosis factor (TNF)-α, interleukin (IL)-6, sarcoplasmic reticulum ATPase (SERCA2a), Na+-Ca2 + exchanger (NCX), ryanodine receptor (RyR), voltage-dependent Ca2 + (CaV1.2), slow-voltage potassium currents (Kvs), angiotensin II type 1 receptor (AT1R), and receptor of advanced glycated end-products (RAGE) from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and SHR treated with sitagliptin (10 mg/kg for 4 weeks). Conventional microelectrodes were used to record action potentials (APs) in the ventricular myocytes from each group. Results Compared to the control group, SHR had lower cardiac PPAR-α and PPAR-δ protein expressions, but had greater cardiac PPAR-γ levels, and TNF-α, IL-6, RAGE, and AT1R protein expressions, which were ameliorated in the sitagliptin-treated SHR. SHR had prolonged QT interval and AP duration with less SERCA2a and RyR, and greater CaV1.2 expressions, which were also attenuated in sitagliptin-treated SHR. Conclusions Sitagliptin significantly changed the cardiac electrophysiological characteristics and Ca2 + regulation, which may have been caused by its effects on cardiac PPARs, proinflammatory cytokines, and AT1R.

KW - Calcium handling

KW - Cardiomyocytes

KW - DPP-4 inhibitor

KW - Hypertension

KW - Sitagliptin

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