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Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases

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Abstract

Remote preconditioning is a unique phenomenon in which brief episodes of ischemia and reperfusion to remote organ protect the target organ against sustained ischemia–reperfusion (I/R)-induced injury. Protective effects of remote renal preconditioning (RRPC) are well established in heart, but their mechanisms still remain to be elucidated. So, the present study was designed to investigate the possible role of oxygen-sensing hypoxia inducible factor-prolyl 4-hydroxylases (HIF-P4Hs) in RRPC-induced cardioprotection in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion and reperfusion. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. Ethyl 3,4-dihydroxybenzoate (EDHB) and α-ketoglutarate (α-KG) were employed as HIF-P4Hs inhibitor and activator, respectively. Diethyldithiocarbamic acid (DDCA) was employed as NFkB inhibitor. Remote renal preconditioning prevented I/R-induced myocardial injury and produced cardioprotective effects. Pharmacological preconditioning with EDHB (100 mg kg−1 i.p.) mimicked the cardioprotective effects of RRPC. However, α-KG (200 mg kg−1 i.p.) and DDCA (150 mg kg−1 i.p.) abolished cardioprotective effects of RRPC and EDHB. So, it may be concluded that inhibition of HIF-P4H has a key role in RRPC-induced cardioprotection. Further, remote preconditioning-induced HIF-P4H inhibition may have triggered a transduction pathway involving activation of NFkB.

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Abbreviations

HIF-P4Hs:

Hypoxia-inducible factor-prolyl 4-hydroxylases

HIF-α:

Hypoxia-inducible factor

EDHB:

Ethyl 3,4-dihydroxybenzoate

NFkB:

Nuclear factor kappa-B

DDCA:

Diethyldithiocarbamic acid

KH:

Kreb’s Henseleit

TTC:

Triphenyl tetrazolium chloride

LDH:

Lactate dehydrogenase

CK:

Creatine kinase

RRPC:

Remote renal preconditioning

I/R:

Ischemia–reperfusion

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Acknowledgments

The authors are grateful to Dr. Ashok Kumar Tiwary, Head, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India for supporting this study and providing technical facilities for the work.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India

    Ravi Kant, Vishal Diwan, Amteshwar Singh Jaggi, Nirmal Singh & Dhandeep Singh

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  1. Ravi Kant
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  2. Vishal Diwan
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  3. Amteshwar Singh Jaggi
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  4. Nirmal Singh
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  5. Dhandeep Singh
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Correspondence to Amteshwar Singh Jaggi.

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Kant, R., Diwan, V., Jaggi, A.S. et al. Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases. Mol Cell Biochem 312, 25–31 (2008). https://doi.org/10.1007/s11010-008-9717-5

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  • DOI: https://doi.org/10.1007/s11010-008-9717-5

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