School of Nursing, PR China.
School of Pharmacy, PR China.
J Ethnopharmacol. 2021 May 23;272:113920. doi: 10.1016/j.jep.2021.113920. Epub 2021 Feb 16.
Pinoresinol diglucoside (PDG), the active compound extracted from Eucommia ulmoides, Styrax sp. and Forsythia suspensa, plays the roles in regulating hypertension, inflammation and oxidative stress.
Considering that hypertension and inflammation has been proved to contribute to cardiac remodeling, we tested the effects of PDG on cardiac hypertrophy (CM).
Male Sprague Dawley (SD) rats were used to construct hypertrophic rats by partial abdominal aortic constriction (AAC)-surgery. PDG solution (2 mg/ml) was used to treat AAC-induced rats by intraperitoneal injection at low dose (L-PDG, 2.5 mg/kg per day), medium dose (M-PDG, 5 mg/kg per day), and high dose (H-PDG, 7.5 mg/kg per day) for 3 weeks post AAC-surgery. CM was evaluated by the ratio of left ventricular weight to body weight ratio (LVW/BW), left ventricular wall thickness by H&E staining, and collagen content deposit by Masson's staining. Further, isoproterenol (ISO) and phenylephrine (PE) were used to produce cellular models of CM in neonatal rat ventricular cardiomyocytes (NRVMs). PDG pre-treated NRVMs 2 h at low dose (L-PDG, 2.5 μg/ml), medium dose (M-PDG, 5 μg/ml), and high dose (H-PDG, 7.5 μg/ml) for 24 h with or without PE- and ISO-stimulation. CM was evaluated by the expressions of hypertrophic biomarkers. Next, the hypertrophic biomarkers and pro-inflammatory cytokines were measured using quantitative real-time PCR (qRT-PCR), the expressions of protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/transcription factor nuclear factor-kappa B (NF-kB) signaling pathway were determined by Western blotting.
PDG treatment prevented cardiac histomorphology damages, decreased upregulations of hypertrophic biomarkers, and prevented fibrosis and inflammation after pressure overload resulting from AAC-surgery. Consistently, PDG remarkably inhibited the changes of cardiomyocyte hypertrophic biomarkers and inflammatory responses in cellular models of CM. Interestingly, PDG administration inhibited the activation of AKT/mTOR/NF-kB signaling pathway both in vivo and in vitro.
PDG prevents AAC-induced CM in vivo, PE- and ISO-induced CM in vitro. The AKT/mTOR/NF-kB signaling pathway could be the potential therapeutic target involved in the protection of PDG. These findings provide novel evidence that PDG might be a promising therapeutic strategy for CM.
松脂醇二葡萄糖苷（PDG）是从杜仲、安息香和连翘中提取的活性化合物，具有调节高血压、炎症和氧化应激的作用。
鉴于高血压和炎症已被证明有助于心脏重构，我们测试了 PDG 对心肌肥厚（CM）的作用。
雄性 Sprague Dawley（SD）大鼠通过腹主动脉部分缩窄（AAC）手术构建肥厚大鼠模型。PDG 溶液（2mg/ml）通过腹腔注射以低剂量（L-PDG，每天 2.5mg/kg）、中剂量（M-PDG，每天 5mg/kg）和高剂量（H-PDG，每天 7.5mg/kg）治疗 AAC 手术后 3 周的 AAC 诱导大鼠。通过左心室重量与体重比（LVW/BW）、H&E 染色的左心室壁厚度和 Masson 染色的胶原蛋白含量沉积评估 CM。此外，异丙肾上腺素（ISO）和苯肾上腺素（PE）用于在新生大鼠心室心肌细胞（NRVMs）中产生 CM 的细胞模型。PDG 在 PE 和 ISO 刺激前预处理 NRVMs 2 小时，低剂量（L-PDG，2.5μg/ml）、中剂量（M-PDG，5μg/ml）和高剂量（H-PDG，7.5μg/ml）24 小时。通过定量实时 PCR（qRT-PCR）测量 CM 的肥大生物标志物，通过 Western blot 测定蛋白激酶 B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）/转录因子核因子-κB（NF-κB）信号通路的表达。
PDG 治疗可预防 AAC 手术后压力超负荷引起的心脏组织形态损伤，降低肥厚生物标志物的上调，并预防纤维化和炎症。一致地，PDG 显著抑制了 CM 细胞模型中心肌肥厚生物标志物和炎症反应的变化。有趣的是，PDG 给药抑制了体内和体外 AKT/mTOR/NF-κB 信号通路的激活。
PDG 可预防 AAC 诱导的体内 CM、PE 和 ISO 诱导的体外 CM。AKT/mTOR/NF-κB 信号通路可能是 PDG 保护作用涉及的潜在治疗靶点。这些发现为 PDG 可能是 CM 的一种有前途的治疗策略提供了新的证据。
