心衰标志物PDE-9A讲义.pptVIP

讲解人：郭君君 The PDE super-family: a).contains 11 sub-genes conferring different cyclic nucleotide and tissue selectivity. b).PDE5A was the first cGMPselective enzyme discovered, and has a major role in erectile and pulmonary vasomotor control. c). PDE9A was cloned 20 years later and has the highest affinity and selectivity for cGMP . d).PDE9A is expressed primarily in the brain, gut and kidney.studies have focused on its role in cognitive function,and mRNA is detectable in the heart and other tissues. 心脏肌肉健康是由两种独立机制(或信号通路)保护 G G Figure 1 . PDE9A expression in heart and myocytes increases with disease. Figure 2. PDE9A inhibition suppresses cardiachypertrophy via natriuretic-peptide–cGMP. PDE-5和PDE-9抑制剂对心功能的影响比较 PE诱发小鼠心衰 前景 精准疗法 PDE5抑制剂对海绵体、肺和体循环系统的血流动力学影响已被充分肯定。大多数对PDE5抑制剂的研究都采用昔多芬, 而伐地那非和他达那非是否也有此类作用还不清楚. 联合疗法 * cGMP PKG 心脏保护性 “制动系统” NP激活 PDE-9 PDE-5 PF-9613 SIL L-Arg +O2 NOS NO + 瓜氨酸 环化酶 通路一 L-NAME DEANO ODQ 环化酶 通路二 DT3 PDE9A upregulation by heart disease suggested its inhibition might blunt pathological stress responses. Thus, opposite to PDE5A, PDE9A hydrolyses cGMP coupled to natriuretic peptide but not nitric oxide stimulation. Figure 3. Pressure-overload-induced cardiac pathobiology is suppressed in Pde9a-/-mice. 结果，缺乏PDE-9的小白鼠表现得更好。与正常的小白鼠心脏相比，缺乏PDE-9的小白鼠心脏有更少的疤痕、肌肉变厚，扩张能力更强。 i, RNCMs exposed to L-NAME and phenylephrine+/-Pde5a siRNA, Pde9a siRNA,or both. PDE-9抑制剂 改善 PDE-5抑制剂 改善 安慰剂 完全心衰 结论:两个通路相辅相成，保护一个通路就可避免疾病发生，即使另一通路出现问题。 *