Na T, Dai D Z, Tang X Y, Dai Y
Research Division of Pharmacology, China Pharmaceutical University, 210009, Nangjing, People's Republic of China.
Naunyn Schmiedebergs Arch Pharmacol. 2007 Mar;375(1):39-49. doi: 10.1007/s00210-007-0134-1. Epub 2007 Feb 8.
Emerging evidence indicates that leptin may be a potential new target in chronic heart failure (CHF) treatment. We hypothesized that hyperleptinemia may correlate with abnormal expression of SERCA2a, PLB (phospholamban), and the endothelin (ET) pathway in CHF. An activated ET pathway is involved in CHF that is suppressed by CPU86017 (p-chlorobenzyltetrahydroberberine chloride), a complex class III antiarrhythmic agent with an antioxidant effect. Thus, relief of CHF may be mediated by a reversal of abnormalities of the leptin system, the ET-reactive oxygen species (ROS) pathway, SERCA2a, and PLB by CPU86017. CHF was produced by coronary artery ligation for 6 weeks in rats. The rats were divided into 3 groups: sham, CHF untreated, and CHF+CPU86017 (4 mg/kg per day, s.c.). Hemodynamic changes, cardiac morphology, serum biochemistry, messenger ribonucleic acid (mRNA) and protein expression of the leptin pathway, ET pathway, and redox were measured. In CHF rats, hemodynamic abnormalities, cardiac remodeling, and histological changes with features of cardiac failure were associated with hyperlipidemia accompanied by oxidative stress and upregulated OB-Rb, ECE, pp-ET-1, ET(A)R, and ET(B)R mRNA expression in the myocardium. Protein expression of leptin and ET(A)R in the myocardium was markedly increased in CHF rats. An activated leptin pathway was associated with downregulation of SERCA2a and upregulation of PLB in mRNA and protein expression in CHF. CPU86017 downregulated the leptin system and reversed the above changes in the myocardium. An activated leptin pathway correlates with abnormal expression of SERCA2a and PLB and an activated ET-ROS system in the affected myocardium. The multi-ion-channel-blocking and antioxidative effects of CPU86017 downregulate the leptin pathway and ET system, resulting in reversal of the abnormalities of expression of SERCA2a and PLB and cardiac performance in CHF.
新出现的证据表明，瘦素可能是慢性心力衰竭（CHF）治疗中的一个潜在新靶点。我们推测，高瘦素血症可能与CHF中肌浆网钙ATP酶2a（SERCA2a）、受磷蛋白（PLB）以及内皮素（ET）途径的异常表达相关。激活的ET途径参与CHF的发生发展，而具有抗氧化作用的Ⅲ类抗心律失常复合药物CPU86017（对氯苄基四氢黄连素氯化物）可抑制该途径。因此，CHF的缓解可能是通过CPU86017逆转瘦素系统、ET-活性氧（ROS）途径、SERCA2a和PLB的异常实现的。通过结扎大鼠冠状动脉6周制备CHF模型。将大鼠分为3组：假手术组、未治疗的CHF组和CHF+CPU86017组（每天4mg/kg，皮下注射）。检测血流动力学变化、心脏形态、血清生化指标、瘦素途径、ET途径及氧化还原相关的信使核糖核酸（mRNA）和蛋白表达。在CHF大鼠中，血流动力学异常、心脏重塑以及具有心力衰竭特征的组织学改变与高脂血症相关，伴有氧化应激，且心肌中OB-Rb、ECE、pp-ET-1、ET(A)R和ET(B)R mRNA表达上调。CHF大鼠心肌中瘦素和ET(A)R的蛋白表达显著增加。在CHF中，激活的瘦素途径与SERCA2a的下调以及PLB在mRNA和蛋白表达上的上调相关。CPU86017下调瘦素系统并逆转心肌中的上述变化。激活的瘦素途径与受累心肌中SERCA2a和PLB的异常表达以及激活的ET-ROS系统相关。CPU86017的多离子通道阻断和抗氧化作用下调瘦素途径和ET系统，导致CHF中SERCA2a和PLB表达异常及心脏功能的逆转。
