Background

Cardiovascular diseases are caused by multitudes of stress factors like hypertension and their outcomes are associated with high mortality and morbidity worldwide. Nerolidol, a naturally occurring sesquiterpene found in several plant species, embodies various pharmacological benefits against numerous health disorders. However, their effects on hypertension induced cardiac complications are not completely understood.

Purpose

The present study is to elucidate the efficacy of nerolidol against hypertension related cardiac hypertrophy in spontaneously hypertensive rats (SHRs).

Study Design

For preliminary in vitro studies, H9c2 cardiomyoblasts cells were challenged with 200 nM Angiotensin-II (AngII) for 12 h and were then treated with nerolidol for 24 h. The hypertrophic effect in H9c2 cells were analyzed by actin staining and the modulations in hypertrophic protein markers and mediators were determined by Western blotting analysis. For in vivo experiments, sixteen week-old male Wistar Kyoto (WKY) and SHRs were segregated into five groups (n = 9): Control WKY, hypertensive SHRs, SHRs with low dose (75 mg/kg b.w/day) nerolidol, SHRs with high dose (150 mg/kg b.w/day) nerolidol and SHR rats treated with an anti-hypertensive drug captopril (50 mg/kg b.w/day). Nerolidol treatment was given orally for 8 weeks and were analysed through Echocardiography. After euthanasia, hematoxylin and eosin staining, Immunohistochemical analysis and Western blotting was performed on left ventricle tissue.

Results

Western blotting analysis revealed that nerolidol significantly attenuates AngII induced expression of hypertrophic markers ANP and BNP in H9c2 cardiomyoblasts. In addition, actin staining further ascertained the potential of nerolidol to ameliorate AngII induced cardiac hypertrophy. Moreover, nerolidol administration suppressed the hypertrophic signalling mediators like calcineurin, GATA4, Mel-18, HSF-2 and IGFIIR in a dose-dependent fashion. In silico studies also ascertained the role of Mel-18 in the ameliorative effects of nerolidol. Further, these intriguing in vitro results were further confirmed in in vivo SHR model. Oral neraolidol in SHRs efficiently reduced blood pressure and ameliorated hypertension induced cardiac hypertrophic effects by effectively reducing the levels of proteins involved in cardiac MeL-18-HSF2-IGF-IIR signalling.

Conclusion

Collectively, the data reveals that the cardioprotective effect of nerolidol against hypertension induced hypertrophy involves reduction in blood pressure and regulation of the cardiac Mel-18-IGFIIR signalling cascade.

中文翻译：

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小分子复合物奈洛尔多通过调节Mel-18-IGF-IIR信号传导减弱自发性高血压大鼠的高血压诱导的肥大

背景

心血管疾病是由多种压力因素引起的，例如高血压，其结果与全球高死亡率和高发病率有关。Nerolidol是一种天然存在的倍半萜烯，存在于几种植物中，对多种健康疾病具有多种药理作用。但是，它们对高血压引起的心脏并发症的作用尚未完全了解。

目的

本研究旨在阐明nerolidol对自发性高血压大鼠（SHRs）与高血压相关的心脏肥大的功效。

学习规划

为了进行初步的体外研究，将H9c2心肌母细胞用200 nM血管紧张素II（AngII）攻击12 h，然后用奈洛多治疗24 h。通过肌动蛋白染色分析H9c2细胞中的肥大作用，并通过蛋白质印迹分析确定肥大蛋白标志物和介体的调节。对于体内实验中，将16周龄的男性Wistar Kyoto（WKY）和SHR分为五组（n = 9）：对照WKY，高血压SHR，低剂量（75 mg / kg bw /天）nerolidol的SHR，高剂量的SHR （150 mg / kg bw /天）nerolidol和SHR大鼠用抗高血压药物卡托普利（50 mg / kg bw /天）治疗。口服给予了Nerolidol治疗8周，并通过超声心动图进行了分析。安乐死后，对左心室组织进行苏木精和曙红染色，免疫组织化学分析和蛋白质印迹。

结果

蛋白质印迹分析表明，nerolidol可显着减弱AngII诱导的H9c2心肌母细胞肥大标志物ANP和BNP的表达。另外，肌动蛋白染色进一步确定了神经olidol改善AngII诱导的心脏肥大的潜力。此外，神经节苷脂的给药以剂量依赖的方式抑制了肥大性信号传导介质，如钙调神经磷酸酶，GATA4，Mel-18，HSF-2和IGFIIR。在计算机研究中，还确定了Mel-18在nerolidol的改善作用中的作用。此外，在体内进一步证实了这些有趣的体外结果SHR模型。通过有效降低心脏MeL-18-HSF2-IGF-IIR信号传导所涉及的蛋白质水平，SHRs中的口服neraolidol可有效降低血压并减轻高血压引起的心肌肥厚效应。

结论

总的来说，该数据表明神经节苷脂对高血压引起的肥大的心脏保护作用涉及血压的降低和心脏Mel-18-IGFIIR信号级联的调节。