Department of Cardiology, The affiliated Hospital of Qingdao University, Qingdao, 266000, China.
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, 250012, China.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Feb;393(2):203-212. doi: 10.1007/s00210-019-01716-0. Epub 2019 Sep 5.
Isorhynchophylline (IRN) is one of the major tetracyclic oxindole alkaloids found in Uncaria rhynchophylla. Studies have found that IRN has diverse biological activities including antioxidant, anti-apoptosis, and neuroprotection. However, little is known about the effect of IRN on the development of cardiac hypertrophy. In this study, we investigated the change of the cell surface area and nascent protein synthesis of cultured H9c2 cardiomyocytes on exposure to phenylephrine (PE) plus IRN, and thus confirmed that IRN ameliorated cardiomyocyte hypertrophy induced by PE in vitro. Meanwhile, it turns out that IRN is also effective in neonatal rat ventricular myocytes (NRVMs) stimulated with angiotensin II (AngII). We also showed that IRN prevented cardiac dysfunction in mice with pressure overload due to transverse aortic constriction (TAC) and attenuated cardiac hypertrophy and fibrosis. IRN treatment improved the cardiac function assessed by echocardiographic parameters fractional shortening (FS) as well as suppressed the cardiac hypertrophy phenotypes, such as the increasing of ventricular mass/body weight and myocyte cross-sectional area. RT-PCR analysis showed that IRN treatment also alleviated the expression of fetal genes of ANP, BNP, Myh7, and the correlated fibrosis genes including TGF-β1, collagen I, collagen III, and CTGF in vivo. Meanwhile, IRN had anti-oxidative effects on cardiac remodeling with suppressed 4-HNE and MDA. Western blot analysis showed that the Nrf2 nuclear translocation and MAPK pathway were involved in the potential mechanisms of IRN on cardiac hypertrophy inhibition. The results of our study provide further evidence that IRN is a promising drug for the treatment of cardiac hypertrophy.
异钩藤碱（IRN）是钩藤中发现的主要四环吲哚生物碱之一。研究发现，IRN 具有多种生物活性，包括抗氧化、抗细胞凋亡和神经保护作用。然而，对于 IRN 对心肌肥大发展的影响知之甚少。在这项研究中，我们研究了在苯肾上腺素（PE）加 IRN 暴露下培养的 H9c2 心肌细胞的细胞表面积和新生蛋白合成的变化，从而证实 IRN 可改善 PE 诱导的体外心肌肥大。同时，事实证明 IRN 对血管紧张素 II（AngII）刺激的新生大鼠心室肌细胞（NRVMs）也有效。我们还表明，IRN 可预防因横主动脉缩窄（TAC）引起的压力超负荷小鼠的心脏功能障碍，并减轻心脏肥大和纤维化。IRN 治疗可通过超声心动图参数缩短分数（FS）评估改善心脏功能，并抑制心室质量/体重增加和心肌细胞横截面积增加等心脏肥大表型。RT-PCR 分析表明，IRN 治疗还可减轻体内 ANP、BNP、Myh7 的胎儿基因以及相关纤维化基因 TGF-β1、胶原 I、胶原 III 和 CTGF 的表达。同时，IRN 对心脏重塑具有抗氧化作用，可抑制 4-HNE 和 MDA。Western blot 分析表明，Nrf2 核易位和 MAPK 途径参与了 IRN 抑制心肌肥大的潜在机制。我们的研究结果进一步证明，IRN 是治疗心肌肥大的一种很有前途的药物。
