Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury?

INTRODUCTION: Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR) injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury. MATERIAL AND METHODS: Levosimendan was administered to male Wistar rats 1 hour (early pretreatment) or 24 hours (late pretreatment) before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR) as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured. RESULTS: In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (pearly = 0.02; plate = 0.005), AST (pearly = 0.02; plate = 0.004) and less DNA damage by TUNEL test (pearly = 0.05; plate = 0.034) and PAR positivity (pearly = 0.02; plate = 0.04). Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment. CONCLUSION: Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection

Endogenous single-strand DNA breaks at RNA polymerase II promoters in <i>Saccharomyces cerevisiae</i>

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Rab11 facilitates crosstalk between autophagy and endosomal pathway through regulation of Hook localization.

During autophagy, double-membrane autophagosomes deliver sequestered cytoplasmic content to late endosomes and lysosomes for degradation. The molecular mechanism of autophagosome maturation is still poorly characterized. The small GTPase Rab11 regulates endosomal traffic, and is thought to function at the level of recycling endosomes. Here we show that loss of Rab11 leads to accumulation of autophagosomes and late endosomes in Drosophila melanogaster. Rab11 translocates from recycling endosomes to autophagosomes in response to autophagy induction, and physically interacts with Hook, a negative regulator of endosome maturation. Hook anchors endosomes to microtubules, and we show that Rab11 facilitates the fusion of endosomes and autophagosomes by removing Hook from mature late endosomes and inhibiting its homodimerization. Thus, induction of autophagy appears to promote autophagic flux by increased convergence with the endosomal pathway

Microcirculatory data of the liver.

<p>S: sham-operated; C_E: “early” control; IR_E: “early” ischemia-reperfusion; L_E: “early” levosimendan pretreated; C_L: “late” control; IR_L: “late” ischemia-reperfusion; L_L: “late” levosimendan pretreated.</p>*<p>p<0.05 versus the respective IR group.</p

Serum level of ALT and AST.

<p>Ischemic-reperfusion injury of the liver led to an increase in serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).A: Serum levels of ALT significantly decreased in the levosimendan pretreated groups (L_E, L_L) compared to the corresponding IR groups (IR_L, IR_E) B: Raised AST activity in the “late” IR group (IR_L) were significantly higher than in the “early” IR group (IR_E). “Late” levosimendan pretreatment significantly reduced the serum activity of AST. Data are shown as means+SEM, * p<0.05 versus “late” IR group; ¤ <0.05 versus “early” IR group; $ p<0.05 versus “late” control group; & p<0.05 versus “early” control group; # p<0.05 versus “early” IR group. n = 5 in sham-operated (S) and control groups (C_E, C_L); n = 10 in IR (IR_L, IR_E) and levosimendan pretreated groups (L_E, L_L).</p