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Fenofibrate attenuates impaired ischemic preconditioning-mediated cardioprotection in the fructose-fed hypertriglyceridemic rat heart

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Abstract

We investigated in this study whether or not the ischemic preconditioning (IPC)-mediated cardioprotective effect against ischemia–reperfusion (I/R) injury exists in the fructose-fed hypertriglyceridemic (HTG) rat heart. Langendorff-perfused normal and fructose-fed (10 % w/v in drinking water, 8 weeks) HTG rat hearts were subjected to 30-min global ischemia and 120-min reperfusion. IPC protocol included four brief episodes (5 min each) of ischemia and reperfusion. Myocardial infarct size using triphenyltetrazolium chloride staining, markers of cardiac injury such as lactate dehydrogenase (LDH) and creatine kinase (CK-MB) release, coronary flow rate (CFR), and myocardial oxidative stress were assessed. High degree of myocardial I/R injury, by means of significant myocardial infarct size, elevated coronary LDH and CK-MB release, reduced CFR, and high oxidative stress, was noted in the HTG rat heart as compared to the normal rat heart. The IPC-mediated cardioprotection against I/R injury was markedly impaired in the HTG rat heart as compared to the normal rat heart. Interestingly, pharmacological reduction of triglycerides using 8-week treatment protocol with fenofibrate (80 mg/kg/day, p.o.) restored the IPC effect in the HTG rat heart that was blunted by coinfusion, during the IPC reperfusion protocol, of a specific inhibitor of phosphoinositide-3-kinase (PI3-K), wortmannin (100 nM). The IPC failed to protect the HTG rat heart against I/R injury. Fenofibrate treatment reduced high triglycerides in the fructose-fed HTG rat and subsequently restored the cardioprotective effect of IPC.

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Abbreviations

Akt:

Protein kinase B

ANOVA:

Analysis of variance

CK-MB:

Creatine kinase isoform MB

DTNB:

5 5′-Dithiobis (2-nitrobenzoic acid)

eNOS:

Endothelial nitric oxide synthase

GSH:

Reduced form of glutathione

Hhcy:

Hyperhomocysteinemia

HTGa:

Hypertriglyceridemia

HTG:

Hypertriglyceridemic

IPC:

Ischemic preconditioning

I/R:

Ischemia–reperfusion

K-H:

Krebs-Hensleit

LDH:

Lactate dehydrogenase

MPTP:

Mitochondrial permeability transition pore

NO:

Nitric oxide

PPARα:

Peroxisome proliferator-activated receptor α

PI3K:

Phosphoinositide-3-kinase

TBARS:

Thiobarbituric acid reactive substance

TTC:

2,3,5-Triphenyltetrazolium chloride

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Acknowledgments

We express our gratitude to Dr. Rajendar Singh Sra, MD, Chairman and Shri Om Parkash, Director, Rajendra Institute of Technology and Sciences, Sirsa, India for their inspiration and constant support for this study. We extend our gratitude to Mr. Sanjeev Kalra for his support during this study.

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Authors and Affiliations

  1. Cardiovascular Pharmacology Division, Department of Pharmacology, Rajendra Institute of Technology and Sciences, Sirsa, 125 055, India

    Lalita Babbar & Pitchai Balakumar

  2. Institute of Pharmacy, Rajendra Institute of Technology and Sciences, Sirsa, 125 055, India

    Nanjaian Mahadevan

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  1. Lalita Babbar
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Correspondence to Pitchai Balakumar.

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Babbar, L., Mahadevan, N. & Balakumar, P. Fenofibrate attenuates impaired ischemic preconditioning-mediated cardioprotection in the fructose-fed hypertriglyceridemic rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 386, 319–329 (2013). https://doi.org/10.1007/s00210-012-0830-3

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