Aldose reductase modulates cardiac glycogen synthase kinase-3 beta phosphorylation during ischemia-reperfusion

作者：Abdillahi Mariane; Ananthakrishnan Radha; Vedantham Srinivasan; Shang Linshan; Zhu Zhengbin; Rosario Rosa; Zirpoli Hylde; Bohren Kurt M; Gabbay Kenneth H; Ramasamy Ravichandran^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2012, 303(3): H297-H308.

DOI：10.1152/ajpheart.00999.2011

• aldose reductase
• ischemia reperfusion
• glycogen synthase kinase 3 beta
• cardioprotection

Abdillahi M, Ananthakrishnan R, Vedantham S, Shang L, Zhu Z, Rosario R, Zirpoli H, Bohren KM, Gabbay KH, Ramasamy R. Aldose reductase modulates cardiac glycogen synthase kinase-3 beta phosphorylation during ischemia-reperfusion. Am J Physiol Heart Circ Physiol 303: H297-H308, 2012. First published June 1, 2012; doi:10.1152/ajpheart.00999.2011.-Earlier studies have demonstrated that aldose reductase (AR) plays a key role in mediating ischemia-reperfusion (I/R) injury. Our objective was to investigate if AR mediates I/R injury by influencing phosphorylation of glycogen synthase kinase-3 beta (p-GSK3 beta). To investigate this issue, we used three separate models to study the effects of stress injury on the heart. Hearts isolated from wild-type (WT), human expressing AR transgenic (ARTg), and AR knockout (ARKO) mice were perfused with/ without GSK3 beta inhibitors (SB-216763 and LiCl) and subjected to I/R. Ad-human AR (Ad-hAR)-expressing HL-1 cardiac cells were exposed to hypoxia (0.5% O-2) and reoxygenation (20.9% O-2) conditions. I/R in a murine model of transient occlusion and reperfusion of the left anterior descending coronary artery (LAD) was used to study if p-GSK3 beta was affected through increased AR flux. Lactate dehydrogenase (LDH) release and left ventricular developed pressure (LVDP) were measured. LVDP was decreased in hearts from ARTg mice compared with WT and ARKO after I/R, whereas LDH release and apoptotic markers were increased (P %26lt; 0.05). p-GSK3 beta was decreased in ARTg hearts compared with WT and ARKO (P %26lt; 0.05). In ARKO, p-GSK3 beta and apoptotic markers were decreased compared with WT (P %26lt; 0.05). WT and ARTg hearts perfused with GSK3 beta inhibitors improved p-GSK3 beta expression and LVDP and exhibited decreased LDH release, apoptosis, and mitochondrial pore opening (P %26lt; 0.05). Ad-hAR-expressing HL-1 cardiac cells, exposed to hypoxia (0.5% O2) and reoxygenation (20.9% O-2), had greater LDH release compared with control HL-1 cells (P %26lt; 0.05). p-GSK3 beta was decreased and correlated with increased apoptotic markers in Ad-hAR HL-1 cells (P %26lt; 0.05). Treatment with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) inhibitor increased injury demonstrated by increased LDH release in ARTg, WT, and ARKO hearts and in Ad-hAR-expressing HL-1 cells. Cells treated with protein kinase C (PKC) alpha/beta inhibitor displayed significant increases in p-Akt and p-GSK3 beta expression, and resulted in decreased LDH release. In summary, AR mediates changes in p-GSK3 beta, in part, via PKC alpha/beta and Akt during I/R.

• 出版日期2012-8