Toghi Cristal Jesus, Martins Laisla Zanetoni, Pacheco Leonardo Lopes, Caetano Edileia Souza Paula, Mattos Bruna Rahal, Rizzi Elen, Dias-Junior Carlos Alan
Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil.
Unit of Biotechnology, University of Ribeirao Preto (UNAERP), Ribeirao Preto 14096-900, SP, Brazil.
Antioxidants (Basel). 2023 Apr 16;12(4):939. doi: 10.3390/antiox12040939.
Pre-eclampsia (PE) is a hypertensive disorder of pregnancy and has been associated with placental growth restriction. The pre-eclamptic placenta releases free radicals to maternal circulation, thus increasing oxidative stress. An impaired redox state leads to reduction in circulating nitric oxide (NO) levels and activation of extracellular matrix metalloproteinases (MMPs). However, activation of MMPs induced by oxidative stress is still unclear in PE. Antioxidant effects have been demonstrated with the use of pravastatin. Therefore, we hypothesized that pravastatin protects against oxidative stress-induced activation of MMPs in a rat model of PE. The animals were divided into four groups: normotensive pregnant rats (Norm-Preg); pregnant rats treated with pravastatin (Norm-Preg + Prava); hypertensive pregnant rats (HTN-Preg); and hypertensive pregnant rats treated with pravastatin (HTN-Preg + Prava). The deoxycorticosterone acetate (DOCA) and sodium chloride (DOCA-salt) model was used to induce hypertension in pregnancy. Blood pressure, and fetal and placental parameters were recorded. The gelatinolytic activity of MMPs, NO metabolites and lipid peroxide levels were also determined. Endothelium function was also examined. Pravastatin attenuated maternal hypertension, prevented placental weight loss, increased NO metabolites, inhibited increases in lipid peroxide levels, and reduced the activity of MMP-2, and these effects were observed along with enhanced endothelium-derived NO-dependent vasodilation. The present results provide evidence that pravastatin protects against activation of MMP-2 induced by oxidative stress in pre-eclamptic rats. These findings may also involve improvement in endothelial function related to NO and antihypertensive effects of pravastatin, thus suggesting pravastatin as a therapeutic intervention for PE.
子痫前期(PE)是一种妊娠期高血压疾病,与胎盘生长受限有关。子痫前期胎盘向母体循环释放自由基,从而增加氧化应激。氧化还原状态受损导致循环中一氧化氮(NO)水平降低和细胞外基质金属蛋白酶(MMPs)激活。然而,在子痫前期中氧化应激诱导MMPs激活的机制仍不清楚。已证实普伐他汀具有抗氧化作用。因此,我们假设普伐他汀可在子痫前期大鼠模型中保护机体免受氧化应激诱导的MMPs激活。将动物分为四组:血压正常的妊娠大鼠(正常妊娠组);用普伐他汀治疗的妊娠大鼠(正常妊娠+普伐他汀组);高血压妊娠大鼠(高血压妊娠组);以及用普伐他汀治疗的高血压妊娠大鼠(高血压妊娠+普伐他汀组)。采用醋酸脱氧皮质酮(DOCA)和氯化钠(DOCA-盐)模型诱导妊娠期高血压。记录血压、胎儿和胎盘参数。还测定了MMPs的明胶酶活性、NO代谢产物和脂质过氧化物水平。同时检测内皮功能。普伐他汀减轻了母体高血压,防止了胎盘重量减轻,增加了NO代谢产物,抑制了脂质过氧化物水平的升高,并降低了MMP-2的活性,并且这些作用伴随着内皮源性NO依赖性血管舒张增强而出现。目前的结果提供了证据表明普伐他汀可保护子痫前期大鼠免受氧化应激诱导的MMP-2激活。这些发现还可能涉及普伐他汀与NO相关的内皮功能改善和降压作用,从而提示普伐他汀可作为子痫前期的一种治疗干预措施。