Abstract
The cardioprotection of the immature heart during cardiac surgery remains controversial due to the differences between the adult heart and the newborn heart. Lysophosphatidic acid (LPA) is a small bioactive molecule with diverse functions including cell proliferation and survival via its receptor: LPA1–LPA6. We previously reported that the expressions of LPA1 and LPA3 in rat hearts were much higher in immature hearts and then declined rapidly with age. In this study, we aimed to investigate whether LPA signaling plays a potential protective role in immature hearts which had experienced ischemia/reperfusion (I/R) injury. The results showed that in Langendorff-perfused immature rat hearts (2 weeks), compared to I/R group, LPA pretreatment significantly enhanced the cardiac function, attenuated myocardial infarct size and CK-MB release, decreased myocardial apoptosis and increased the expression of pro-survival signaling molecules. All these effects could be abolished by Ki16425, an antagonist to LPA1 and LPA3. Similarly, LPA pretreatment protected H9C2 from hypoxia-reoxygenation (H/R) induced apoptosis and necrosis in vitro. The mechanisms underlying the anti-apoptosis effects were related to activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinas B (AKT) signaling pathways as well as phosphorylation of the downstream effector of AKT, glycogen synthase kinase 3 beta (GSK3β), through LPA1 and/or LPA3. What's more, we found that LPA preconditioning increased glucose uptake of H9C2 subjected to H/R by the activation of AMP-Activated Protein Kinase (AMPK) but not the translocation of GLUT4. In conclusion, our study indicates that LPA is a potent survival factor for immature hearts against I/R injuries and has the potential therapeutic function as a cardioplegia additive for infantile cardiac surgery.
Highlights
Similar cardioprotection methods have been used in adult and pediatric groups for many years (Turkoz, 2013)
Lysophosphatidic acid (LPA), a bioactive molecule released by activated platelets under pathological conditions, is involved in cardiovascular disease (Abdel-Latif et al, 2015)
Our previous study has documented that LPA protects mesenchymal stem cells against ischemiainduced apoptosis (Chen et al, 2008) and LPA1 and LPA3 are highly expressed during the neonatal period (Wang et al, 2012)
Summary
Similar cardioprotection methods have been used in adult and pediatric groups for many years (Turkoz, 2013). The immature heart is structurally, functionally, and metabolically different to the adult heart. The immature heart mainly prefers to utilize glucose as its energy source rather than free fatty acids—which is the main substrate in the normal adult heart (∼70%) (Onay-Besikci, 2006; Calmettes et al, 2015). Cardioprotection of LPA in Immature Heart tolerant to ischemia, it is more vulnerable to reactive oxygen species after reperfusion than the adult heart (Starnes et al, 1997). Nowadays the optimal myocardial protection strategy for newborns undergoing congenital heart surgery remains controversial. It is necessary to explore an optimal myocardial protection strategy for the immature heart
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