PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer.
PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer.
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DOI：
10.1016/j.pharmthera.2014.10.003
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发表时间：
2015-03
影响因子：
13.5
通讯作者：
Kukreja, Rakesh C.
中科院分区：
文献类型：
--
作者：
Das, Anindita;Durrant, David;Salloum, Fadi N.;Xi, Lei;Kukreja, Rakesh C.
磷酸二酯酶5（PDE 5）抑制剂，包括西地那非（Viagra™）、伐地那非（Levitra™）和他达拉非（Cialis™），已经被开发用于治疗勃起功能障碍。此外，西地那非和他达拉非用于管理患者的肺动脉高压。自从我们在2002年首次报告西地那非的心脏保护作用以来，关于PDE 5抑制剂用于心血管疾病和癌症的临床前和临床研究有了巨大的增长。大量动物实验表明，PDE 5抑制剂对心肌缺血/再灌注（I/R）损伤、阿霉素心脏毒性、缺血性和糖尿病性心肌病、心肌肥大、Duchenne肌营养不良症具有强大的保护作用，并能提高干细胞修复心肌的功效。从机制上讲，PDE 5抑制剂通过增加一氧化氮合酶的表达、激活蛋白激酶G（PKG）、PKG依赖性硫化氢生成和紧邻线粒体通透性转换孔和心脏保护末端效应器的糖原合成酶激酶-3 β - a主开关磷酸化来保护心脏免受I/R损伤。此外，PDE 5抑制剂增强了某些类型的癌症对标准化疗药物（包括阿霉素）的敏感性。许多PDE 5抑制剂的临床试验都集中在潜在的心血管和癌症益处上。尽管这些临床试验的结果好坏参半，但基础科学家和临床研究人员对探索其新的临床用途仍然抱有浓厚的兴趣。我们希望未来新的机制研究和精心设计的临床试验将有助于获得PDE 5抑制剂对心血管疾病和癌症患者的额外益处。
The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and cancer benefits. Despite mixed results of these clinical trials, there is continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients.
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影响因子：
2.1
作者：
Ferrini, Monica G.;Davila, Hugo H.;Rajfer, Jacob
通讯作者：
Rajfer, Jacob
DOI：
10.1152/ajpheart.00654.2010
发表时间：
2011-06-01
影响因子：
4.8
作者：
Chau, Vinh Q.;Salloum, Fadi N.;Kukreja, Rakesh C.
通讯作者：
Kukreja, Rakesh C.
DOI：
10.1073/pnas.0705891104
发表时间：
2007-09-25
影响因子：
11.1
作者：
Elrod, John W.;Calvert, John W.;Lefer, David J.
通讯作者：
Lefer, David J.
影响因子：
2.9
作者：
Black, Keith L.;Yin, Dali;Ong, John M.;Hu, Jinwei;Konda, Bindu M.;Wang, Xiao;Ko, MinHee K.;Bayan, Jennifer-Ann;Sacapano, Manuel R.;Espinoza, Andreas;Irvin, Dwain K.;Shu, Yan
通讯作者：
Shu, Yan
影响因子：
37.8
作者：
Fisher, PW;Salloum, F;Kukreja, RC
通讯作者：
Kukreja, RC