B-type natriuretic peptide expression and cardioprotection is regulated by Akt dependent signaling at early reperfusion

Abstract

Exogenously administered B-type natriuretic peptide (BNP) has been shown to offer cardioprotection through activation of particulate guanylyl cyclase (pGC), protein kinase G (PKG) and KATP channel opening. The current study explores if cardioprotection afforded by short intermittent BNP administration involves PI3K/Akt/p70s6k dependent signaling, and whether this signaling pathway may participate in regulation of BNP mRNA expression at early reperfusion. Isolated Langendorff perfused rat hearts were subjected to 30min of regional ischemia and 120min of reperfusion (IR). Applying intermittent 3×30s infusion of BNP peptide in a postconditioning like manner (BNPPost) reduced infarct size by >50% compared to controls (BNPPost 17±2% vs. control 42±4%, p<0.001). Co-treatment with inhibitors of the PI3K/Akt/p70s6k pathway (wortmannin, SH-6 and rapamycin) completely abolished the infarct-limiting effect of BNP postconditioning (BNPPost+Wi 36±5%, BNPPost+SH-6 41±4%, BNPPost+Rap 37±6% vs. BNPPost 17±2%, p<0.001). Inhibition of natriuretic peptide receptors (NPR) by isatin also abrogated BNPPost cardioprotection (BNPPost+isatin 46±2% vs. BNPPost 17±2%, p<0.001). BNPPost also significantly phosphorylated Akt and p70s6k at early reperfusion, and Akt phosphorylation was inhibited by SH-6 and isatin. Myocardial BNP mRNA levels in the area at risk (AA) were significantly elevated at early reperfusion as compared to the non-ischemic area (ANA) (Ctr(AA) 2.7±0.5 vs. Ctr(ANA) 1.2±0.2, p<0.05) and the ischemic control tissue (Ctr(AA) 2.7±0.5 vs. ischemia 1.0±0.1, p<0.05). Additional experiments also revealed a significant higher BNP mRNA level in ischemic postconditioned (IPost) hearts as compared to ischemic controls (IPost 6.7±1.3 vs. ischemia 1.0±0.2, p<0.05), but showed no difference from controls run in parallel (Ctr 5.4±0.8). Akt inhibition by SH-6 completely abrogated this elevation (IPost 6.7±1.3 vs. IPost+SH-6 1.8±0.7, p<0.05) (Ctr 5.4±0.8 vs. SH-6 1.5±0.9, p<0.05). In conclusion, Akt dependent signaling is involved in mediating the cardioprotection afforded by intermittent BNP infusion at early reperfusion, and may also participate in regulation of reperfusion induced BNP expression.

Lebetin 2, a Snake Venom-Derived Natriuretic Peptide, Attenuates Acute Myocardial Ischemic Injury through the Modulation of Mitochondrial Permeability Transition Pore at the Time of Reperfusion

“…We found that L2 enhanced phosphorylated PKCε/ERK/GSK3β and PI3K/Akt/eNOS expression suggesting that both cGMP/PKG-dependent and independent pathways are involved in the L2-induced effects during IR. This is in agreement with recent data reporting that protective action of BNP in IR could involve PI3K/Akt/eNOS and PKCε/GSK3β pathways [ 5 , 6 , 14 ]. This further documents the similarity of action between L2 and BNP.…”

“…Mechanisms involved in the effect of BNP in ischemia include activation of natriuretic peptide receptor type A (NPR-A) and stimulation of guanylyl cyclase (GC) to increase intracellular cyclic guanosine monophosphate (cGMP)-dependent protein kinase G (PKG) pathway [ 11 ] and subsequent triggering of mitochondrial K ATP (mitoK ATP ) channel opening [ 5 , 12 ]. However, growing evidence suggests that BNP could activate a cGMP-independent pathway by binding to Gi-protein coupled natriuretic peptide receptor type C (NPR-C) [ 13 ] and activating downstream PI3K/Akt/eNOS and MAPK/ERK pathways [ 5 , 6 , 14 ]. Mitochondria is recognized to have a critical role during myocardial IR in promoting both necrosis and apoptosis in association with opening of mitochondrial permeability transition pore (mPTP) and subsequent release of apoptotic signaling molecules.…”

Association of platelet-to-lymphocyte count ratio with myocardial reperfusion and major adverse events in patients with acute myocardial infarction: a two-centre retrospective cohort study

“…BNP has been shown to be an independent risk factor for IR injury in ST-segment elevation AMI patients 39. Studies have shown that the increased secretion of BNP during myocardial ischaemia is mainly regulated by the PI3K/Akt/p70s6k signalling pathway, which has a protective effect on the myocardium 40. This change is an adaptation of myocardial cells to ischaemia.…”

Potential Molecular Mechanism of the NPPB Gene in Post-Ischemic Heart Failure with and without T2DM

“…Alcohol abuse may increase times risk of chronic HF than the one who do not has alcohol abuse [51], and the BNP level would increase markedly [34]. In context to PI3K-Akt signaling pathway, it has been revealed involved in the expression level of BNP and the cardio-protection afforded by BNP infusion [52,53]. Thus, these pathways and the genes enriched in would affect the level of BNP and the development of HF.…”