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Zerumbone prevents pressure overload-induced left ventricular systolic dysfunction by inhibiting cardiac hypertrophy and fibrosis
Phytomedicine ( IF 7.9 ) Pub Date : 2021-09-14 , DOI: 10.1016/j.phymed.2021.153744
Nurmila Sari 1 , Yasufumi Katanasaka 2 , Yuga Sugiyama 1 , Yoichi Sunagawa 2 , Yusuke Miyazaki 1 , Masafumi Funamoto 1 , Satoshi Shimizu 1 , Kana Shimizu 1 , Akira Murakami 3 , Kiyoshi Mori 1 , Hiromichi Wada 4 , Koji Hasegawa 4 , Tatsuya Morimoto 2
Affiliation  

Background

Cardiac hypertrophy and fibrosis are hallmarks of cardiac remodeling and are involved functionally in the development of heart failure (HF). However, it is unknown whether Zerumbone (Zer) prevents left ventricular (LV) systolic dysfunction by inhibiting cardiac hypertrophy and fibrosis.

Purpose

This study investigated the effect of Zer on cardiac hypertrophy and fibrosis in vitro and in vivo.

Study Design/methods

In primary cultured cardiac cells from neonatal rats, the effect of Zer on phenylephrine (PE)-induced hypertrophic responses and transforming growth factor beta (TGF-β)-induced fibrotic responses was observed. To determine whether Zer prevents the development of pressure overload-induced HF in vivo, a transverse aortic constriction (TAC) mouse model was utilized. Cardiac function was evaluated by echocardiography. The changes of cardiomyocyte surface area were observed using immunofluorescence staining and histological analysis (HE and WGA staining). Collagen synthesis and fibrosis formation were measured by scintillation counter and picrosirius staining, respectively. The total mRNA levels of genes associated with hypertrophy (ANF and BNP) and fibrosis (Postn and α-SMA) were measured by qRT-PCR. The protein expressions (Akt and α-SMA) were assessed by western blotting.

Results

Zer significantly suppressed PE-induced increase in cell size, mRNA levels of ANF and BNP, and Akt phosphorylation in cardiomyocytes. The TGF-β-induced increase in proline incorporation, mRNA levels of Postn and α-SMA, and protein expression of α-SMA were decreased by Zer in cultured cardiac fibroblasts. In the TAC male C57BL/6 mice, echocardiography results demonstrated that Zer improved cardiac function by increasing LV fractional shortening and reducing LV wall thickness compared with the vehicle group. ZER significantly reduced the level of phosphorylated Akt both in cultured cardiomyocytes treated with PE and in the hearts of TAC. Finally, Zer inhibited the pressure overload-induced cardiac hypertrophy and cardiac fibrosis.

Conclusion

Zer ameliorates pressure overload-induced LV dysfunction, at least in part by suppressing both cardiac hypertrophy and fibrosis.



中文翻译:

Zerumbone 通过抑制心脏肥大和纤维化来预防压力超负荷引起的左心室收缩功能障碍

背景

心脏肥大和纤维化是心脏重塑的标志,并且在功能上参与了心力衰竭 (HF) 的发展。然而,Zerumbone (Zer) 是否通过抑制心脏肥大和纤维化来预防左心室 (LV) 收缩功能障碍尚不清楚。

目的

本研究在体外体内研究了 Zer 对心脏肥大和纤维化的影响。

研究设计/方法

在来自新生大鼠的原代培养的心脏细胞中,观察到 Zer 对苯肾上腺素 (PE) 诱导的肥大反应和转化生长因子 β (TGF-β) 诱导的纤维化反应的影响。确定 Zer 是否能防止体内压力超负荷诱发的 HF 的发展,使用横向主动脉缩窄 (TAC) 小鼠模型。通过超声心动图评估心脏功能。使用免疫荧光染色和组织学分析(HE和WGA染色)观察心肌细胞表面积的变化。分别通过闪烁计数器和天狼星染色测量胶原合成和纤维化形成。通过qRT-PCR测量与肥大(ANF和BNP)和纤维化(Postn和α-SMA)相关的基因的总mRNA水平。通过蛋白质印迹评估蛋白质表达(Akt 和α-SMA)。

结果

Zer 显着抑制 PE 诱导的细胞大小、ANF 和 BNP 的 mRNA 水平以及心肌细胞中 Akt 磷酸化的增加。TGF-β 诱导的脯氨酸掺入增加、Postn 和 α-SMA 的 mRNA 水平以及 α-SMA 的蛋白质表达在培养的心脏成纤维细胞中被 Zer 降低。在 TAC 雄性 C57BL/6 小鼠中,超声心动图结果表明,与载体组相比,Zer 通过增加 LV 缩短部分和减少 LV 壁厚来改善心脏功能。ZER 显着降低了用 PE 处理的培养心肌细胞和 TAC 心脏中磷酸化 Akt 的水平。最后,Zer 抑制了压力超负荷引起的心脏肥大和心脏纤维化。

结论

Zer 改善了压力超负荷引起的 LV 功能障碍,至少部分是通过抑制心脏肥大和纤维化。

更新日期:2021-09-23
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