C33(S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling
C33(S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling
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C33(S) 是一种新型 PDE9A 抑制剂，通过上调 cGMP 信号传导防止大鼠心脏肥大
DOI：
10.1038/aps.2017.38
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发表时间：
2017-09-01
影响因子：
8.2
通讯作者：
Liu, Pei-qing
中科院分区：
文献类型：
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作者：
Wang, Pan-xia;Li, Zhuo-ming;Liu, Pei-qing
磷酸二酯酶-9A（PDE 9A）的表达在心脏肥大和心力衰竭期间上调。越来越多的证据表明，PDE 9A可能是一个有前途的治疗心脏疾病的目标。本研究旨在探讨新型选择性PDE 9A抑制剂C33（S）在体内外对心肌肥厚的影响及其机制。用PE（100 μ mol/L）或ISO（1 μ mol/L）处理新生大鼠心肌细胞（NRCM）可诱导心肌肥大，其特征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显着增加PDE 9A在细胞中的表达，而PDE 9A的敲低显着减轻PE诱导的肥大反应。此外，PDE 9A抑制剂C33（S）（50和500 nmol/L）或PF-7943（2 μ mol/L）预处理也减轻了PE处理的NRCM的心脏肥大反应。建立SD大鼠腹主动脉缩窄（AAC）诱导的心肌肥厚模型和ISO诱导的心力衰竭模型。在ISO处理的大鼠中，口服C33（S）（9、3和1mg.kg天，连续3周）显著增加缩短分数（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），但左心室内径减小，表明C33（S）延迟了向心力衰竭的转变。我们进一步揭示了C33（S）在体外PE处理的NRCM和体内ISO诱导的心力衰竭模型中显著升高细胞内cGMP水平、受磷蛋白（PLB）磷酸化和SERCA 2a表达。我们的研究结果表明，C33（S）有效地防止心脏肥大，并推迟向心力衰竭的转变，这表明它是一种有前途的药物在治疗心脏疾病。
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 mu mol/L) or ISO (1 mu mol/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 mu mol/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(-1).d(-1), 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.