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

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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.

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Abbreviations

Ale:

Aleglitazar

Glim:

Glimeperide

GTT:

Glucose tolerance test

HCMs:

Human cardiomyocytes

mCM-WT:

Cardiomyocytes from wild type

LDH:

Lactate dehydrogenase

MTT:

Thiazolyl blue tetrazolium bromide

NSIR:

No simulated ischemia reperfusion

PPARα:

Proliferator-activated receptor-α

PPARγ:

Peroxisome proliferator-activated receptor- γ

PPARγ CKO:

Cardiomyocytes from cardiac-specific PPARγ knockout mice

SDS:

Sodium Dodecyl sulfate

siPPARα:

siRNA against PPARα

siPPARγ:

siRNA against PPARγ

SIR:

Simulated ischemia reperfusion

T2DM:

Type 2 diabetes mellitus.

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Acknowledgments

This work was supported by the grants from F. Hoffmann-La Roche Ltd, National Natural Science Foundation of China (81160035 and 81460044), Yunnan Provincial Science and Technology Department (2014HB031 and 2011FZ119) and Yunnan Provincial Bureau of Health (D201211).

Authors’ Contributions

JQ and HC carried out the cellular and in vivo studies and participated in drafted the manuscript. MKM and BT carried out the immunoblotting study and performed the statistical analysis. YB and MB interpreted the data and reviewed the manuscript. JQ, YB, and YY conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

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    Authors and Affiliations

    1. Department of Anesthesiology, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China

      Jinqiao Qian

    2. Department of Anesthesiology, Kunming Tongren Hospital, Kunming, Yunnan Province, China

      Hongmei Chen

    3. Department of Medicine, Section of Cardiology, Baylor College of Medicine, One Baylor Plaza, MS BCM620, Houston, TX, USA

      Yochai Birnbaum

    4. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA

      Yochai Birnbaum, Manjyot K. Nanhwan & Yumei Ye

    5. Department of Medicine, Section of Endocrinology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

      Mandeep Bajaj

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    Jinqiao Qian and Hongmei Chen contributed equally to this work.

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    Qian, J., Chen, H., Birnbaum, Y. et al. Aleglitazar, a Balanced Dual PPARα and -γ Agonist, Protects the Heart Against Ischemia-Reperfusion Injury. Cardiovasc Drugs Ther 30, 129–141 (2016). https://doi.org/10.1007/s10557-016-6650-9

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