The Cardioprotective Properties and Signaling Pathway of Myocardial BNP

Background: Coronary heart disease is one of the leading causes of death in the world, and mainly arises from ischemic heart disease. The most effective treatment for mortality reduction in patients with coronary occlusion is myocardial reperfusion. However, reperfusion itself can cause cell death by a phenomenon known as lethal reperfusion injury. B-type natriuretic peptide (BNP) is a peptide hormone released from the ventricles of the heart that has properties that protect the heart cells from lethal reperfusion injury. Objective: The first aim of this study was to determine if treatment with BNP in a postconditioning like manner would provide cardioprotection by reducing infarct size in the isolated ex vivo female rat heart when administered as three 30 second bursts immediately following ischemia-reperfusion. The second aim was to investigate if this cardioprotection is dependent on the RISK signaling pathway and the natriuretic peptide receptors (NPR). Methods: Female rat hearts were Langendorff perfused and subjected to 30 min of regional ischemia and 120 min reperfusion. At the onset of reperfusion they were infused for 3 x 30 sec with BNP in a postconditioning like manner (BNPPost). Inhibitors of PI3K, Akt, and p70s6k (Wortmannin, SH-6, and Rapamycin) in the RISK signaling pathway and the NPR-inhibitor Isatin were used to determine if these components are required for BNPPost to induce cardioprotection. Results: BNPPost reduced infarct size by ~50% compared to controls. Inhibitors of the RISK pathway abrogated the cardioprotection afforded by BNP. BNP cardioprotection was also abolished by the NPR-inhibitor Isatin. BNPPost also resulted in a significant phosphorylation of Akt and p70s6k at early reperfusion compared to controls. Conclusion: BNP postconditioning provides cardioprotection against ischemia-reperfusion injury via an NPR receptor and PI3K/Akt/p70s6k-dependent RISK signalling.