Background

Angiotensin II (Ang II)-induced cardiac inflammation contribute to pathological cardiac remodeling and hypertensive heart failure (HF). Tabersonine (Tab) is an indole alkaloid mainly isolated from Catharanthus roseus and exhibits anti-inflammatory activity in various systems. However, the role of Tab in hypertensive HF and its molecular targets remains unknown.

Hypothesis/purpose

We aimed to investigate potential cardioprotective effects and mechanism of Tab against Ang II-induced cardiac injuries.

Methods

C57BL/6 mice were administered Ang II (at 1000 ng/kg/min) by micro-osmotic pump infusion for 30 days to develop hypertensive HF. Tab at 20 and 40 mg/kg/day was administered during the last 2 weeks to elucidate the cardioprotective properties. Cultured cardiomyocyte-like H9c2 cells and rat primary cardiomyocytes were used for mechanistic studies of Tab.

Results

We demonstrate for the first time that Tab provides protection against Ang II–induced cardiac dysfunction in mice, associated with reduced cardiac inflammation and fibrosis. Mechanistically, we show that Tab may interacts with TAK1 to inhibit Ang II-induced TAK1 ubiquitination and phosphorylation. Disruption of TAK1 activation by Tab blocked downstream NF-κB and JNK/P38 MAPK signaling activation and decreased cardiac inflammation and fibrosis both in vitro and in vivo. TAK1 knockdown also blocked Ang II-induced cardiomyocytes injuries and prevented the innately pharmacological effects of Tab.

Conclusion

Our results indicate that Tab protects hearts against Ang II-mediated injuries through targeting TAK1 and inhibiting TAK1-mediated inflammatory cascade and response. Thus, Tab may be a potential therapeutic candidate for hypertensive HF.

中文翻译：

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Tabersonine 通过靶向 TAK1 和抑制 TAK1 介导的心脏炎症减轻血管紧张素 II 诱导的心脏重塑和功能障碍

背景

血管紧张素 II (Ang II) 诱导的心脏炎症有助于病理性心脏重塑和高血压性心力衰竭 (HF)。Tabersonine (Tab) 是一种吲哚生物碱，主要从长春花中分离出来，在各种系统中表现出抗炎活性。然而，Tab 在高血压 HF 中的作用及其分子靶点仍然未知。

假设/目的

我们旨在研究 Tab 对 Ang II 诱导的心脏损伤的潜在心脏保护作用和机制。

方法

C57BL/6 小鼠通过微渗透泵输注给予 Ang II（1000 ng/kg/min）30 天，以发展高血压 HF。在最后 2 周期间以 20 和 40 mg/kg/天的剂量给药以阐明心脏保护特性。培养的心肌细胞样 H9c2 细胞和大鼠原代心肌细胞用于 Tab 的机制研究。

结果

我们首次证明 Tab 可以保护小鼠免受 Ang II 诱导的心脏功能障碍，这与减少心脏炎症和纤维化有关。从机制上讲，我们表明 Tab 可能与 TAK1 相互作用以抑制 Ang II 诱导的 TAK1 泛素化和磷酸化。Tab 对 TAK1 激活的破坏阻断了下游 NF-κB 和 JNK/P38 MAPK 信号传导的激活，并在体外和体内减少了心脏炎症和纤维化。TAK1 敲低还阻断了 Ang II 诱导的心肌细胞损伤并阻止了 Tab 的先天药理作用。

结论

我们的结果表明，Tab 通过靶向 TAK1 和抑制 TAK1 介导的炎症级联反应和反应来保护心脏免受 Ang II 介导的损伤。因此，Tab 可能是高血压 HF 的潜在治疗候选者。