Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes

Yumei Ye, Jinqiao Qian, Alexander C. Castillo, Shukuan Ling, Hongmei Ye, Jose R. Perez-Polo, Mandeep Bajaj, Yochai Birnbaum

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Glucagon-like peptide (GLP)-1 receptor activation increases intracellular cAMP with downstream activation of PKA. Cilostazol (CIL), a phosphodiesterase-3 inhibitor, prevents cAMP degradation. We assessed whether CIL amplifies the exenatide (EX)-induced increase in myocardial cAMP levels and PKA activity and augments the infarct size (IS)-limiting effects of EX in db/db mice. Mice fed a Western diet received oral CIL (10 mg/kg) or vehicle by oral gavage 24 h before surgery. One hour before surgery, mice received EX (1 μg/kg sc) or vehicle. Additional mice received H-89, a PKA inhibitor, alone or with CIL + EX. Mice underwent 30 min of coronary artery occlusion and 24 h of reperfusion. Both EX and CIL increased myocardial cAMP levels and PKA activity. Levels were significantly higher in the EX + CIL group. Both EX and CIL reduced IS. IS was the smallest in the CIL + EX group. H-89 completely blocked the IS-limiting effects of EX + CIL. EX + CIL decreased phosphatase and tensin homolog on chromosome 10 upregulation and increased Akt and ERK1/2 phosphorylation after ischemiareperfusion. These effects were blocked by H-89. In conclusion, EX and CIL have additive effects on IS limitation in diabetic mice. The additive effects are related to cAMP-induced PKA activation, as H-89 blocked the protective effect of CIL + EX.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number1
DOIs
StatePublished - Jan 1 2013

Fingerprint

Phosphoric Diester Hydrolases
Type 2 Diabetes Mellitus
Myocardial Infarction
cilostazol
exenatide
Phosphodiesterase 3 Inhibitors
Chromosomes, Human, Pair 10
Coronary Occlusion
Phosphoric Monoester Hydrolases
Reperfusion
Coronary Vessels
Up-Regulation
Phosphorylation

Keywords

  • cAMP
  • Cilostazol
  • Glucagon-like peptide-1
  • Infarct size
  • Phosphatase and tensin homolog on chromosome 10
  • Phosphdiesterase-3 inhibitor
  • Protein kinase A

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes. / Ye, Yumei; Qian, Jinqiao; Castillo, Alexander C.; Ling, Shukuan; Ye, Hongmei; Perez-Polo, Jose R.; Bajaj, Mandeep; Birnbaum, Yochai.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 304, No. 1, 01.01.2013.

Research output: Contribution to journalArticle

Ye, Yumei ; Qian, Jinqiao ; Castillo, Alexander C. ; Ling, Shukuan ; Ye, Hongmei ; Perez-Polo, Jose R. ; Bajaj, Mandeep ; Birnbaum, Yochai. / Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes. In: American Journal of Physiology - Heart and Circulatory Physiology. 2013 ; Vol. 304, No. 1.
@article{e0570f622cdd4ca28f1d8d8c14ff0265,
title = "Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes",
abstract = "Glucagon-like peptide (GLP)-1 receptor activation increases intracellular cAMP with downstream activation of PKA. Cilostazol (CIL), a phosphodiesterase-3 inhibitor, prevents cAMP degradation. We assessed whether CIL amplifies the exenatide (EX)-induced increase in myocardial cAMP levels and PKA activity and augments the infarct size (IS)-limiting effects of EX in db/db mice. Mice fed a Western diet received oral CIL (10 mg/kg) or vehicle by oral gavage 24 h before surgery. One hour before surgery, mice received EX (1 μg/kg sc) or vehicle. Additional mice received H-89, a PKA inhibitor, alone or with CIL + EX. Mice underwent 30 min of coronary artery occlusion and 24 h of reperfusion. Both EX and CIL increased myocardial cAMP levels and PKA activity. Levels were significantly higher in the EX + CIL group. Both EX and CIL reduced IS. IS was the smallest in the CIL + EX group. H-89 completely blocked the IS-limiting effects of EX + CIL. EX + CIL decreased phosphatase and tensin homolog on chromosome 10 upregulation and increased Akt and ERK1/2 phosphorylation after ischemiareperfusion. These effects were blocked by H-89. In conclusion, EX and CIL have additive effects on IS limitation in diabetic mice. The additive effects are related to cAMP-induced PKA activation, as H-89 blocked the protective effect of CIL + EX.",
keywords = "cAMP, Cilostazol, Glucagon-like peptide-1, Infarct size, Phosphatase and tensin homolog on chromosome 10, Phosphdiesterase-3 inhibitor, Protein kinase A",
author = "Yumei Ye and Jinqiao Qian and Castillo, {Alexander C.} and Shukuan Ling and Hongmei Ye and Perez-Polo, {Jose R.} and Mandeep Bajaj and Yochai Birnbaum",
year = "2013",
month = "1",
day = "1",
doi = "10.1152/ajpheart.00609.2012",
language = "English (US)",
volume = "304",
journal = "American Journal of Physiology - Endocrinology and Metabolism",
issn = "0193-1849",
publisher = "American Physiological Society",
number = "1",

}

TY - JOUR

T1 - Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes

AU - Ye, Yumei

AU - Qian, Jinqiao

AU - Castillo, Alexander C.

AU - Ling, Shukuan

AU - Ye, Hongmei

AU - Perez-Polo, Jose R.

AU - Bajaj, Mandeep

AU - Birnbaum, Yochai

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Glucagon-like peptide (GLP)-1 receptor activation increases intracellular cAMP with downstream activation of PKA. Cilostazol (CIL), a phosphodiesterase-3 inhibitor, prevents cAMP degradation. We assessed whether CIL amplifies the exenatide (EX)-induced increase in myocardial cAMP levels and PKA activity and augments the infarct size (IS)-limiting effects of EX in db/db mice. Mice fed a Western diet received oral CIL (10 mg/kg) or vehicle by oral gavage 24 h before surgery. One hour before surgery, mice received EX (1 μg/kg sc) or vehicle. Additional mice received H-89, a PKA inhibitor, alone or with CIL + EX. Mice underwent 30 min of coronary artery occlusion and 24 h of reperfusion. Both EX and CIL increased myocardial cAMP levels and PKA activity. Levels were significantly higher in the EX + CIL group. Both EX and CIL reduced IS. IS was the smallest in the CIL + EX group. H-89 completely blocked the IS-limiting effects of EX + CIL. EX + CIL decreased phosphatase and tensin homolog on chromosome 10 upregulation and increased Akt and ERK1/2 phosphorylation after ischemiareperfusion. These effects were blocked by H-89. In conclusion, EX and CIL have additive effects on IS limitation in diabetic mice. The additive effects are related to cAMP-induced PKA activation, as H-89 blocked the protective effect of CIL + EX.

AB - Glucagon-like peptide (GLP)-1 receptor activation increases intracellular cAMP with downstream activation of PKA. Cilostazol (CIL), a phosphodiesterase-3 inhibitor, prevents cAMP degradation. We assessed whether CIL amplifies the exenatide (EX)-induced increase in myocardial cAMP levels and PKA activity and augments the infarct size (IS)-limiting effects of EX in db/db mice. Mice fed a Western diet received oral CIL (10 mg/kg) or vehicle by oral gavage 24 h before surgery. One hour before surgery, mice received EX (1 μg/kg sc) or vehicle. Additional mice received H-89, a PKA inhibitor, alone or with CIL + EX. Mice underwent 30 min of coronary artery occlusion and 24 h of reperfusion. Both EX and CIL increased myocardial cAMP levels and PKA activity. Levels were significantly higher in the EX + CIL group. Both EX and CIL reduced IS. IS was the smallest in the CIL + EX group. H-89 completely blocked the IS-limiting effects of EX + CIL. EX + CIL decreased phosphatase and tensin homolog on chromosome 10 upregulation and increased Akt and ERK1/2 phosphorylation after ischemiareperfusion. These effects were blocked by H-89. In conclusion, EX and CIL have additive effects on IS limitation in diabetic mice. The additive effects are related to cAMP-induced PKA activation, as H-89 blocked the protective effect of CIL + EX.

KW - cAMP

KW - Cilostazol

KW - Glucagon-like peptide-1

KW - Infarct size

KW - Phosphatase and tensin homolog on chromosome 10

KW - Phosphdiesterase-3 inhibitor

KW - Protein kinase A

UR - http://www.scopus.com/inward/record.url?scp=84871851596&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871851596&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00609.2012

DO - 10.1152/ajpheart.00609.2012

M3 - Article

C2 - 23103492

AN - SCOPUS:84871851596

VL - 304

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 1

ER -