CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload-Induced Heart Failure.
CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload-Induced Heart Failure.
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DOI：
10.1161/circheartfailure.120.007300
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Blanton RM
中科院分区：
文献类型：
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作者：
Richards DA;Aronovitz MJ;Liu P;Martin GL;Tam K;Pande S;Karas RH;Bloomfield DM;Mendelsohn ME;Blanton RM
增强利钠肽受体和环鸟苷酸 (cGMP) 信号传导已成为心力衰竭 (HF) 的治疗策略。在临床前研究中，环 GMP 特异性磷酸二酯酶 9 (PDE9) 抑制可增加 cGMP 信号传导并减轻应激诱发的肥厚性心脏病。一种新型 cGMP 特异性 PDE9 抑制剂 CRD-733 目前正在人体临床研究中取得进展。在这里，我们探讨了 CRD-733 慢性 PDE9 抑制对小鼠横主动脉缩窄 (TAC) 压力超载心力衰竭模型的影响。成年雄性 C57BL/6J 小鼠接受 TAC 治疗，7 天后出现明显的左心室 (LV) 肥厚 (P<0.001)。然后，小鼠每天接受 CRD-733（600 毫克/公斤/天；n=10）或媒介物（n=17）以及假手术对照（n=10）的治疗。通过连续超声心动图评估，与媒介物相比，CRD-733治疗逆转了现有的左心室肥厚（P<0.001），显着改善了左心室射血分数（P=0.009）并减弱了左心房扩张（P<0.001）。与媒介物相比，CRD-733 可防止左心室舒张末压升高（P=0.037），同时肺重量（肺水肿的替代指标）降低至假手术水平。与媒介物相比，慢性 CRD-733 治疗增加了血浆 cGMP 水平（P<0.001），同时心肌肌球蛋白结合蛋白-C（一种 cGMP 依赖性蛋白激酶 I 磷酸化位点）的 Ser273 磷酸化增加。 PDE9 抑制剂 CRD-733 可改善小鼠 TAC 心力衰竭模型中心力衰竭的关键特征，包括左心室肥厚、左心室功能障碍、左心房扩张和压力超负荷后的肺水肿。此外，升高的血浆 cGMP 可以用作目标参与的生物标志物。这些发现支持未来对 CRD-733 在人类心力衰竭治疗潜力的研究。
Augmentation of natriuretic peptide receptor and cyclic GMP (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). Cyclic GMP-specific phosphodiesterase 9 (PDE9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction (TAC) pressure overload HF model. Adult male C57BL/6J mice were subjected to TAC and developed significant left ventricular (LV) hypertrophy after 7 days (P<0.001). Mice then received daily treatment with CRD-733 (600mg/kg/day; n=10) or vehicle (n=17), alongside sham-operated controls (n=10). CRD-733 treatment reversed existing LV hypertrophy compared to vehicle (P<0.001), significantly improved LV ejection fraction (P=0.009) and attenuated left atrial dilation (P<0.001), as assessed by serial echocardiography. CRD-733 prevented elevations in LV end diastolic pressures (P=0.037) compared to vehicle, whilst lung weights, a surrogate for pulmonary edema, were reduced to sham levels. Chronic CRD-733 treatment increased plasma cGMP levels compared to vehicle (P<0.001), alongside increased phosphorylation of Ser273 of cardiac myosin binding protein-C, a cGMP-dependent protein kinase I phosphorylation site. The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation and pulmonary edema after pressure overload in the mouse TAC HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.