Aleglitazar, a Balanced Dual PPARα and -γ Agonist, Protects the Heart Against Ischemia-Reperfusion Injury

Jinqiao Qian, Hongmei Chen, Yochai Birnbaum, Manjyot K. Nanhwan, Mandeep Bajaj, Yumei Ye

Research output: Contribution to journalArticle

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Abstract

Purpose: To evaluate whether aleglitazar (Ale), a dual PPARα/γ agonist, has additive effects on myocardial protection against ischemia-reperfusion injury. Methods: Human cardiomyocytes (HCMs), cardiomyocytes from cardiac-specific PPARγ knockout (MCM-PPARγCKO) or wild type (MCM-WT) mice were incubated with different concentrations of Ale, and subjected to simulated ischemia-reperfusion (SIR) or normoxic conditions (NSIR). Cell viability, apoptosis and caspase-3 activity were determined. HCMs were transfected with siRNA against PPARα (siPPARα) or PPARγ (siPPARγ) followed by incubation with Ale. PPARα/γ DNA binding capacity was measured. Cell viability, apoptosis and levels of P-AKT and P-eNOS were assessed. Infarct size following 30 min coronary artery occlusion and 24 h reperfusion were assessed in WT and db/db diabetic mice following 3-day pretreatment with vehicle, Ale or glimeperide. Results: Ale (at concentrations of 150–600 nM) increased cell viability and reduced apoptosis in HCMs, MCM-WT and MCM-PPARCKO exposed to SIR. In HCM, the protective effect was partially blocked by siPPARα alone or siPPARγ alone, and completely blocked by siPPARα+siPPARγ. Ale increased P-Akt/P-eNOS in HCMs. P-Akt or P-eNOS levels were decreased when PPARα alone, PPARγ alone and especially when both were knocked down. Peritoneal GTTs revealed that db/db mice had developed impaired glucose tolerance and insulin sensitivity, which were normalized by Ale or glimepiride treatment. Ale, but not glimepiride, limited infarct size in both WT and diabetic mice after ischemia-reperfusion. Conclusions: Ale protects against myocardial apoptosis caused by hypoxia-reoxygenation in vitro and reduces infarct size in vivo.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalCardiovascular Drugs and Therapy
DOIs
StateAccepted/In press - Feb 10 2016

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Peroxisome Proliferator-Activated Receptors
Reperfusion Injury
Cardiac Myocytes
Small Interfering RNA
glimepiride
Reperfusion
Apoptosis
Cell Survival
Ischemia
aleglitazar
Glucose Intolerance
Coronary Occlusion
Caspase 3
Insulin Resistance
Coronary Vessels

Keywords

  • Aleglitazar
  • Cardioprotection
  • Diabetes mellitus
  • Hypoxia-reoxygenation injury
  • Infarct size
  • Ischemia-reperfusion
  • PPARα, PPARγ

ASJC Scopus subject areas

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

Cite this

Aleglitazar, a Balanced Dual PPARα and -γ Agonist, Protects the Heart Against Ischemia-Reperfusion Injury. / Qian, Jinqiao; Chen, Hongmei; Birnbaum, Yochai; Nanhwan, Manjyot K.; Bajaj, Mandeep; Ye, Yumei.

In: Cardiovascular Drugs and Therapy, 10.02.2016, p. 1-13.

Research output: Contribution to journalArticle

Qian, Jinqiao ; Chen, Hongmei ; Birnbaum, Yochai ; Nanhwan, Manjyot K. ; Bajaj, Mandeep ; Ye, Yumei. / Aleglitazar, a Balanced Dual PPARα and -γ Agonist, Protects the Heart Against Ischemia-Reperfusion Injury. In: Cardiovascular Drugs and Therapy. 2016 ; pp. 1-13.
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AU - Qian, Jinqiao

AU - Chen, Hongmei

AU - Birnbaum, Yochai

AU - Nanhwan, Manjyot K.

AU - Bajaj, Mandeep

AU - Ye, Yumei

PY - 2016/2/10

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N2 - Purpose: To evaluate whether aleglitazar (Ale), a dual PPARα/γ agonist, has additive effects on myocardial protection against ischemia-reperfusion injury. Methods: Human cardiomyocytes (HCMs), cardiomyocytes from cardiac-specific PPARγ knockout (MCM-PPARγCKO) or wild type (MCM-WT) mice were incubated with different concentrations of Ale, and subjected to simulated ischemia-reperfusion (SIR) or normoxic conditions (NSIR). Cell viability, apoptosis and caspase-3 activity were determined. HCMs were transfected with siRNA against PPARα (siPPARα) or PPARγ (siPPARγ) followed by incubation with Ale. PPARα/γ DNA binding capacity was measured. Cell viability, apoptosis and levels of P-AKT and P-eNOS were assessed. Infarct size following 30 min coronary artery occlusion and 24 h reperfusion were assessed in WT and db/db diabetic mice following 3-day pretreatment with vehicle, Ale or glimeperide. Results: Ale (at concentrations of 150–600 nM) increased cell viability and reduced apoptosis in HCMs, MCM-WT and MCM-PPARCKO exposed to SIR. In HCM, the protective effect was partially blocked by siPPARα alone or siPPARγ alone, and completely blocked by siPPARα+siPPARγ. Ale increased P-Akt/P-eNOS in HCMs. P-Akt or P-eNOS levels were decreased when PPARα alone, PPARγ alone and especially when both were knocked down. Peritoneal GTTs revealed that db/db mice had developed impaired glucose tolerance and insulin sensitivity, which were normalized by Ale or glimepiride treatment. Ale, but not glimepiride, limited infarct size in both WT and diabetic mice after ischemia-reperfusion. Conclusions: Ale protects against myocardial apoptosis caused by hypoxia-reoxygenation in vitro and reduces infarct size in vivo.

AB - Purpose: To evaluate whether aleglitazar (Ale), a dual PPARα/γ agonist, has additive effects on myocardial protection against ischemia-reperfusion injury. Methods: Human cardiomyocytes (HCMs), cardiomyocytes from cardiac-specific PPARγ knockout (MCM-PPARγCKO) or wild type (MCM-WT) mice were incubated with different concentrations of Ale, and subjected to simulated ischemia-reperfusion (SIR) or normoxic conditions (NSIR). Cell viability, apoptosis and caspase-3 activity were determined. HCMs were transfected with siRNA against PPARα (siPPARα) or PPARγ (siPPARγ) followed by incubation with Ale. PPARα/γ DNA binding capacity was measured. Cell viability, apoptosis and levels of P-AKT and P-eNOS were assessed. Infarct size following 30 min coronary artery occlusion and 24 h reperfusion were assessed in WT and db/db diabetic mice following 3-day pretreatment with vehicle, Ale or glimeperide. Results: Ale (at concentrations of 150–600 nM) increased cell viability and reduced apoptosis in HCMs, MCM-WT and MCM-PPARCKO exposed to SIR. In HCM, the protective effect was partially blocked by siPPARα alone or siPPARγ alone, and completely blocked by siPPARα+siPPARγ. Ale increased P-Akt/P-eNOS in HCMs. P-Akt or P-eNOS levels were decreased when PPARα alone, PPARγ alone and especially when both were knocked down. Peritoneal GTTs revealed that db/db mice had developed impaired glucose tolerance and insulin sensitivity, which were normalized by Ale or glimepiride treatment. Ale, but not glimepiride, limited infarct size in both WT and diabetic mice after ischemia-reperfusion. Conclusions: Ale protects against myocardial apoptosis caused by hypoxia-reoxygenation in vitro and reduces infarct size in vivo.

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