Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou 510006, China.
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Acta Pharmacol Sin. 2017 Sep;38(9):1257-1268. doi: 10.1038/aps.2017.38. Epub 2017 Jun 26.
Phosphodiesterase-9A (PDE9A) expression is upregulated during cardiac hypertrophy and heart failure. Accumulating evidence suggests that PDE9A might be a promising therapeutic target for heart diseases. The present study sought to investigate the effects and underlying mechanisms of C33(S), a novel selective PDE9A inhibitor, on cardiac hypertrophy in vitro and in vivo. Treatment of neonatal rat cardiomyocytes (NRCMs) with PE (100 μmol/L) or ISO (1 μmol/L) induced cardiac hypertrophy characterized by significantly increased cell surface areas and increased expression of fetal genes (ANF and BNP). Furthermore, PE or ISO significantly increased the expression of PDE9A in the cells; whereas knockdown of PDE9A significantly alleviated PE-induced hypertrophic responses. Moreover, pretreatment with PDE9A inhibitor C33(S) (50 and 500 nmol/L) or PF-7943 (2 μmol/L) also alleviated the cardiac hypertrophic responses in PE-treated NRCMs. Abdominal aortic constriction (AAC)-induced cardiac hypertrophy and ISO-induced heart failure were established in SD rats. In ISO-treated rats, oral administration of C33(S) (9, 3, and 1 mg·kg·d, for 3 consecutive weeks) significantly increased fractional shortening (43.55%±3.98%, 54.79%±1.95%, 43.98%±7.96% vs 32.18%±6.28%), ejection fraction (72.97%±4.64%, 84.29%±1.56%, 73.41%±9.37% vs 49.17%±4.20%) and cardiac output (60.01±9.11, 69.40±11.63, 58.08±8.47 mL/min vs 48.97±2.11 mL/min) but decreased the left ventricular internal diameter, suggesting that the transition to heart failure was postponed by C33(S). We further revealed that C33(S) significantly elevated intracellular cGMP levels, phosphorylation of phospholamban (PLB) and expression of SERCA2a in PE-treated NRCMs in vitro and in ISO-induced heart failure model in vivo. Our results demonstrate that C33(S) effectively protects against cardiac hypertrophy and postpones the transition to heart failure, suggesting that it is a promising agent in the treatment of cardiac diseases.
磷酸二酯酶 9A（PDE9A）在心肌肥厚和心力衰竭期间表达上调。越来越多的证据表明，PDE9A 可能是心脏病治疗的一个有前途的靶点。本研究旨在探讨新型选择性 PDE9A 抑制剂 C33(S) 在体外和体内对心肌肥厚的作用及其潜在机制。用 PE（100 μmol/L）或 ISO（1 μmol/L）处理新生大鼠心肌细胞（NRCMs）可诱导心肌肥厚，表现为细胞表面积显著增加和胎儿基因（ANF 和 BNP）表达增加。此外，PE 或 ISO 显著增加了细胞中 PDE9A 的表达；而 PDE9A 的敲低显著减轻了 PE 诱导的心肌肥厚反应。此外，用 PDE9A 抑制剂 C33(S)（50 和 500 nmol/L）或 PF-7943（2 μmol/L）预处理也减轻了 PE 处理的 NRCMs 中的心肌肥厚反应。在 SD 大鼠中建立了腹主动脉缩窄（AAC）诱导的心肌肥厚和 ISO 诱导的心力衰竭模型。在 ISO 处理的大鼠中，连续 3 周口服 C33(S)（9、3 和 1 mg·kg·d）显著增加了短轴缩短率（43.55%±3.98%、54.79%±1.95%、43.98%±7.96%vs 32.18%±6.28%）、射血分数（72.97%±4.64%、84.29%±1.56%、73.41%±9.37%vs 49.17%±4.20%）和心输出量（60.01±9.11、69.40±11.63、58.08±8.47 mL/min vs 48.97±2.11 mL/min），但降低了左心室内径，提示 C33(S) 推迟了心力衰竭的转变。我们进一步表明，C33(S) 显著提高了 PE 处理的 NRCMs 中的细胞内 cGMP 水平、磷蛋白（PLB）的磷酸化和 SERCA2a 的表达以及 ISO 诱导的心力衰竭模型体内的表达。我们的结果表明，C33(S) 能有效防治心肌肥厚并推迟心力衰竭的转变，表明它是一种有前途的心脏病治疗药物。
