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

作　　者：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 

机构地区：[1]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 [2]School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China

出　　处：《Acta Pharmacologica Sinica》2017年第9期1257-1268,共12页中国药理学报（英文版）

摘　　要：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 inPhosphodiesterase-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

关 键 词：cardiac hypertrophy CARDIOMYOCYTES PDE9A C33（S） PF-7943 CGMP PHOSPHOLAMBAN SERCA2A 

分 类 号：Q463[生物学—生理学] Q421