Lee Eunjo, Song Min-Ji, Lee Hae-Ahm, Kang Seol-Hee, Kim Mina, Yang Eun Kyoung, Lee Do Young, Ro Seonggu, Cho Joong Myung, Kim Inkyeom
Department of Pharmacology, Kyungpook National University School of Medicine, Daegu 41944, Korea.; Cardiovascular Research Institute, Kyungpook National University School of Medicine, Daegu 41944, Korea.; Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu 41944, Korea.; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University School of Medicine, Daegu 41944, Korea.
Department of Pharmacology, Kyungpook National University School of Medicine, Daegu 41944, Korea.
Korean J Physiol Pharmacol. 2016 Sep;20(5):477-85. doi: 10.4196/kjpp.2016.20.5.477. Epub 2016 Aug 26.
CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.
CG200745是一种新型组蛋白去乙酰化酶（HDAC）抑制剂，最初开发用于治疗各种血液系统癌症和实体癌。由于它是水溶性的，所以可以口服给药。我们推测HDAC抑制剂CG200745可减轻醋酸脱氧皮质酮（DOCA）诱导的高血压大鼠的心脏肥大和纤维化。为了建立高血压模型，每周皮下注射40mg/kg的DOCA，共4次，注射到Sprague-Dawley大鼠体内。本研究中使用的所有大鼠，包括假手术组的大鼠，均进行了单侧肾切除术，并允许它们自由饮用含1%氯化钠的饮用水。通过尾套法测量收缩压。分析包括钠、钾、葡萄糖、甘油三酯和胆固醇水平在内的血液生化指标。用三色染色法以及苏木精和伊红染色法观察心脏切片。通过定量实时PCR（qRT-PCR）测量肥大基因如心房利钠肽A（Nppa）和心房利钠肽B（Nppb）以及纤维化基因如胶原蛋白-1、胶原蛋白-3、结缔组织生长因子（Ctgf）和纤连蛋白的表达。注射DOCA可增加收缩压、心脏重量和心脏纤维化，而CG200745可减轻这些变化。DOCA和CG200745均不影响体重、血管收缩和舒张反应以及血液生化指标。注射DOCA可增加肥大基因和纤维化基因的表达，而CG200745可消除这种增加。这些结果表明，CG200745可减轻DOCA诱导的高血压大鼠的心脏肥大和纤维化。
