C33（S）, a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling

• Published in: 中国药理学报：英文版 Vol. 38; no. 9; pp. 1257 - 1268
• Main Author: Pan-xia WANG Zhuo-ming LI Si-dong CAI Jing-yan LI Ping HE Yi HUANG Guo-shuai FENG Hai-bin LUO Shao-rui CHEN Pei-qing LIU
• Format: Journal Article
• Language: English
• Published: 2017
• Subjects: C33; cGMP; 心力衰竭; 心肌肥厚; 抑制剂; 新生大鼠; 细胞治疗; 蛋白磷酸化
• ISSN: 1671-4083; 1745-7254

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 pmol/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 I 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.