Beltowski Jerzy, Jamroz-Wiśniewska Anna, Borkowska Ewelina, Wójcicka Grazyna
Department of Pathophysiology, Medical University, ul. Jaczewskiego 8, 20-090 Lublin, Poland.
Pharmacol Res. 2005 Jun;51(6):523-32. doi: 10.1016/j.phrs.2005.01.007.
Recent studies suggest that adipose tissue hormone, leptin, is involved in atherogenesis, especially in obese subjects. Previously, we have demonstrated that experimentally induced hyperleptinemia decreases plasma paraoxonase 1 (PON1) activity. The aim of this study was to investigate whether treatment with synthetic antioxidant, Tempol, modulates the effect of leptin on plasma and tissue PON1 in the rat. Leptin was administered at a dose of 0.25 mgkg-1 s.c. twice daily for 7 days and Tempol was added to the drinking water at a concentration of 2 mM. Leptin reduced plasma PON1 activity toward paraoxon, phenyl acetate and gamma-decanolactone to 71.1, 72.3 and 57.1% of control, respectively. In addition, leptin decreased PON1 activity toward paraoxon in aorta, renal cortex and medulla to 78.6, 49.2 and 48.0% of control, respectively, but had no effect on PON1 in heart, lung and liver. PON1 activity toward phenyl acetate was lower following leptin treatment only in aorta. Leptin increased plasma concentration and urinary excretion of isoprostanes as well as malonyldialdehyde + 4-hydroxyalkenals level in aorta, renal cortex and renal medulla. Coadministration of Tempol prevented leptin-induced oxidative stress and normalized PON1 activity in aorta and kidney. However, Tempol had no effect on plasma PON1 in leptin-treated rats. These data indicate that hyperleptinemia decreases tissue PON1 activity through oxidative stress-dependent mechanism. In contrast, leptin-induced downregulation of plasma PON1 is not mediated by oxidative stress.
近期研究表明，脂肪组织激素瘦素参与动脉粥样硬化的形成，在肥胖个体中尤为如此。此前，我们已证明实验诱导的高瘦素血症会降低血浆对氧磷酶1（PON1）的活性。本研究的目的是调查合成抗氧化剂Tempol的治疗是否能调节瘦素对大鼠血浆和组织中PON1的影响。瘦素以0.25 mgkg-1的剂量皮下注射，每日两次，共7天，Tempol以2 mM的浓度添加到饮用水中。瘦素使血浆中PON1对对氧磷、苯乙酸和γ-癸内酯的活性分别降至对照组的71.1%、72.3%和57.1%。此外，瘦素使主动脉、肾皮质和髓质中PON1对对氧磷的活性分别降至对照组的78.6%、49.2%和48.0%，但对心脏、肺和肝脏中的PON1没有影响。瘦素处理后，仅主动脉中PON1对苯乙酸的活性降低。瘦素增加了血浆中异前列腺素的浓度和尿排泄量，以及主动脉、肾皮质和肾髓质中丙二醛+4-羟基烯醛的水平。同时给予Tempol可预防瘦素诱导的氧化应激，并使主动脉和肾脏中的PON1活性恢复正常。然而，Tempol对瘦素处理大鼠的血浆PON1没有影响。这些数据表明，高瘦素血症通过氧化应激依赖性机制降低组织PON1活性。相比之下，瘦素诱导的血浆PON1下调不是由氧化应激介导的。
