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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 28, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp134
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Role of B-type Natriuretic Peptide in Epoxyeicosatrienoic Acid Mediated Improved Postischemic Recovery of Heart Contractile Function

Ketul R. Chaudhary1, Sri Nagarjun Batchu1, Dipankar Das1, Mavanur R. Suresh1, John R. Falck2, Joan P. Graves3, Darryl C. Zeldin3 and John M. Seubert1

1 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
2 Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX
3 Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC.

Corresponding Author: John M. Seubert, PhD, Faculty of Pharmacy, University of Alberta, Edmonton, AB, T6G 2N8, Phone: 780-492-0007, Fax: 780-492-1217, E-mail: jseubert{at}pharmacy.ualberta.ca

Aims: This study examined the functional role of B-type natriuretic peptide (BNP) in epoxyeicosatrienoic acid (EET)-mediated cardioprotection in mice with targeted disruption of the sEH or Ephx2 gene (sEH null).

Method: Isolated mouse hearts were perfused in the Langendorff mode and subjected to global no-flow ischemia followed by reperfusion. Hearts were analyzed for recovery of left ventricular developed pressure (LVDP), mRNA levels and protein expression.

Results: Naïve hearts from sEH null mice had similar expression of preproBNP (Nppb) mRNA compared to wild-type (WT) hearts. However, significant increases in Nppb mRNA and BNP protein expression occurred during postischemic reperfusion and correlated with improved postischemic recovery of LVDP. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid prior to ischemia reduced the preproBNP mRNA in sEH null hearts. Inhibitor studies demonstrated that perfusion with the natriuretic peptide receptor type-A (NPR-A) antagonist, A71915 [GenBank] , limited the improved recovery in recombinant full-length mouse BNP (rBNP)- and 11,12-EET-perfused hearts as well as in sEH null mice. Increased expression of phosphorylated protein kinase C {epsilon} and Akt were found in WT hearts perfused with either 11,12-EET or rBNP, while mitochondrial glycogen synthase kinase-3β was significantly lower in the same samples. Furthermore, treatment with the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin abolished improved LVDP recovery in 11,12-EET-treated hearts but not did significantly inhibit recovery of rBNP treated hearts.

Conclusion: Taken together, these data indicate that EET-mediated cardioprotection involves BNP and PI3K signaling events.

Time for primary review: 24 Days


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