Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
J Cardiovasc Pharmacol. 2013 Apr;61(4):337-44. doi: 10.1097/FJC.0b013e318283a565.
The incidence, prevalence, and hospitalization rates associated with heart failure (HF) are projected to increase substantially in the world. Among all medications used clinically to treat HF, valsartan (VAL) and spironolactone (SPL) have been shown to reduce morbidity and mortality. Recently, a novel cardiac gene cardiotrophin-1 (CT-1) has been shown to play a crucial role in the pathogenesis of HF. However, the ability of VAL and SPL to modulate the expression of CT-1 has not been investigated yet. Therefore, healthy and isoproterenol (ISO)-induced hypertrophy adult male Wistar albino rats were treated with either VAL or SPL for 14 days. Thereafter, cardiac markers of cardiotoxicity and hypertrophy, creatine kinase, heart weight/body weight ratio, and atrial natriuretic peptide mRNA levels were measured. In addition, CT-1 mRNA and protein levels were determined by real-time polymerase chain reaction and Western blot analysis. Our results showed that the increases in all HF markers, creatine kinase, heart weight/body weight ratio, and atrial natriuretic peptide mRNA levels in ISO-treated rats were significantly restored to their normal levels by VAL and SPL. In addition, induction of cardiac hypertrophy by ISO caused remarkable induction in CT-1 mRNA and protein expression levels by approximately 3.5- and 3-fold, respectively. Importantly, VAL and SPL significantly decreased the induction of CT-1 gene at the mRNA and protein levels in heart hypertrophied rats. On the other hand, treatment of cardiac-derived rat myoblast H9c2 cells with VAL and SPL significantly decreased angiotensin II-induced CT-1 mRNA levels through transcriptional mechanism, as demonstrated by the effect of transcription inhibitor, actinomycin D. In conclusion, VAL and SPL exhibited their cardioprotective effect through inhibiting the expression of CT-1 gene in cardiac hypertrophied rats.
心力衰竭（HF）的发病率、患病率和住院率预计将在全球范围内大幅上升。在所有用于临床治疗 HF 的药物中，缬沙坦（VAL）和螺内酯（SPL）已被证明可降低发病率和死亡率。最近，一种新型心脏基因心营养素-1（CT-1）已被证明在 HF 的发病机制中发挥关键作用。然而，VAL 和 SPL 调节 CT-1 表达的能力尚未得到研究。因此，用 VAL 或 SPL 治疗健康和异丙肾上腺素（ISO）诱导的成年雄性 Wistar 白化大鼠 14 天。此后，测量了心脏毒性和肥大的标志物、肌酸激酶、心脏重量/体重比和心房利钠肽 mRNA 水平。此外，通过实时聚合酶链反应和 Western blot 分析测定 CT-1 mRNA 和蛋白水平。我们的结果表明，ISO 处理大鼠的所有 HF 标志物、肌酸激酶、心脏重量/体重比和心房利钠肽 mRNA 水平的升高均被 VAL 和 SPL 显著恢复到正常水平。此外，ISO 引起的心脏肥大导致 CT-1 mRNA 和蛋白表达水平分别约增加 3.5 倍和 3 倍。重要的是，VAL 和 SPL 显著降低了心脏肥大大鼠 CT-1 基因在 mRNA 和蛋白水平上的诱导。另一方面，VAL 和 SPL 处理心脏衍生大鼠成肌细胞 H9c2 细胞可通过转录机制显著降低血管紧张素 II 诱导的 CT-1 mRNA 水平，如转录抑制剂放线菌素 D 的作用所示。总之，VAL 和 SPL 通过抑制心脏肥大大鼠 CT-1 基因的表达表现出其心脏保护作用。
