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

Abstract

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.

Ameliorative Role of Fluconazole Against Abdominal Aortic Constriction–Induced Cardiac Hypertrophy in Rats

“…The characteristic molecular and echocardiography data pertinent to the AAC model in rats in this study completely aligned with previous studies that have used the same model for induction of cardiac hypertrophy in rats. [36][37][38] The initial novel finding of this study was that fluconazole was able ameliorate the AAC-induced cardiac hypertrophy. This finding is evidenced by the capability of fluconazole to normalize all the changes of the cardiac hypertrophic markers to nearly control levels.…”

“…The characteristic molecular and echocardiography data pertinent to the AAC model in rats in this study completely aligned with previous studies that have used the same model for induction of cardiac hypertrophy in rats. 36–38…”

Nuclear Localization Leucine-Rich-Repeat Protein 1 Deficiency Protects Against Cardiac Hypertrophy by Pressure Overload

“…The ablation of NLRP1 alleviated pathological cardiac hypertrophy and dysfunction in response to pressure overload. Numerous factors, such as Ang-II, PE, ET-1, catecholamines, growth factors, and TNF-α, can induce ventricular hypertrophy [23][24][25]. On the cellular level, the expression of the NLRP1 protein was higher after treatment with PE.…”

Evaluation of phosphodiesterase 9A as a novel biomarker in heart failure with preserved ejection fraction

“…However, the authors used lung samples from rats as a positive control, and hence, the specificity of this antibody for human samples needs further investigation. Notably, recent investigations also identified cardiac PDE9A expression in two rat HF models induced by abdominal aortic constriction or isoproterenol treatment, as well as in myocardium and thoracic aorta from rabbits fed with a high‐cholesterol diet 13,14 …”