Senolytic Agent Navitoclax Inhibits Angiotensin II-Induced Heart Failure in Mice
Senolytic Agent Navitoclax Inhibits Angiotensin II-Induced Heart Failure in Mice
复制标题
抗衰老剂 Navitoclax 抑制血管紧张素 II 诱导的小鼠心力衰竭
DOI：
10.1097/fjc.0000000000000878
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发表时间：
2020-10
影响因子：
3
通讯作者：
Jin Qi
中科院分区：
文献类型：
--
作者：
Jia Kangni;Dai Yang;Liu Ao;Li Xiang;Wu Liqun;Lu Lin;Bao Yangyang;Jin Qi
Navitoclax是一种衰老药物，选择性地消除衰老细胞。本研究旨在评价navitoclax治疗血管紧张素II（Ang II）诱导的小鼠心力衰竭的治疗潜力。在患有Ang II诱导的心力衰竭的小鼠中施用Navitoclax或媒介物。在给药前和给药后评估心功能和电生理。在心肌组织中分析心脏重构，包括形态学变化、纤维化和炎症反应。在体外分离的原代心肌细胞和心脏成纤维细胞中验证了navitoclax的细胞作用。小鼠的超声心动图显示，navitoclax通过改善左心室射血分数来改善心功能不全（赋形剂：45.88 +/-2.19%; navitoclax：54.70 +/-1.65%，P <0.01）。在心脏电生理测试中，navitoclax增加传导速度（载体：1.37 +/-0.05 mm/ms; navitoclax：1.69 +/-0.08 mm/ms，P <0.05），并降低对程控电刺激诱导的室性快速性心律失常的易感性。组织学染色、免疫荧光和蛋白质印迹检测显示，navitoclax改善了Ang II诱导的心脏纤维化、肥大和炎症反应。此外，navitoclax消除衰老细胞诱导凋亡。因此，navitoclax通过减少心力衰竭小鼠的心脏纤维化、肥大和炎症改善了心脏功能和电生理特征。衰老细胞的药理学清除可能是射血分数降低的心力衰竭的潜在治疗方法。
Navitoclax, which is a type of senolytic drug, selectively eliminates senescent cells. This study aimed to evaluate the therapeutic potential of navitoclax in treatment of angiotensin II (Ang II)-induced heart failure in mice. Navitoclax or vehicle was administrated in mice with Ang II-induced heart failure. Cardiac function and electrophysiology were assessed before and after administration of navitoclax. Cardiac remodeling, including morphological changes, fibrosis, and inflammatory responses, was analyzed in myocardial tissue. Cellular effects of navitoclax were validated in isolated primary cardiomyocytes and cardiac fibroblasts in vitro. Echocardiography of mice showed that navitoclax improved cardiac dysfunction by improving the left ventricular ejection fraction (vehicle: 45.88 +/- 2.19%; navitoclax: 54.70 +/- 1.65%, P < 0.01). In cardiac electrophysiological testing, navitoclax increased conduction velocity (vehicle: 1.37 +/- 0.05 mm/ms; navitoclax: 1.69 +/- 0.08 mm/ms, P < 0.05) and decreased susceptibility to ventricular tachyarrhythmia induced by programmed electrical stimulation. Histopathological staining, immunofluorescence, and western blotting examinations showed that navitoclax ameliorated Ang II-induced cardiac fibrosis, hypertrophy, and the inflammatory response. Moreover, navitoclax eliminated senescent cells by inducing apoptosis. Therefore, navitoclax improved cardiac function and electrophysiological characteristics through decreasing cardiac fibrosis, hypertrophy, and inflammation in mice with heart failure. Pharmacological clearance of senescent cells may be a potential therapeutic approach in heart failure with reduced ejection fraction.
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影响因子：
20.1
作者：
Ismahil MA;Hamid T;Bansal SS;Patel B;Kingery JR;Prabhu SD
通讯作者：
Prabhu SD
影响因子：
17.1
作者：
Lagares D;Santos A;Grasberger PE;Liu F;Probst CK;Rahimi RA;Sakai N;Kuehl T;Ryan J;Bhola P;Montero J;Kapoor M;Baron M;Varelas X;Tschumperlin DJ;Letai A;Tager AM
通讯作者：
Tager AM
影响因子：
5.8
作者：
Tanai, Edit;Frantz, Stefan
通讯作者：
Frantz, Stefan
DOI：
10.1038/nrd.2017.116
发表时间：
2017-10
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Childs BG;Gluscevic M;Baker DJ;Laberge RM;Marquess D;Dananberg J;van Deursen JM
通讯作者：
van Deursen JM
DOI：
10.1158/1078-0432.ccr-11-3090
发表时间：
2012-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Rudin CM;Hann CL;Garon EB;Ribeiro de Oliveira M;Bonomi PD;Camidge DR;Chu Q;Giaccone G;Khaira D;Ramalingam SS;Ranson MR;Dive C;McKeegan EM;Chyla BJ;Dowell BL;Chakravartty A;Nolan CE;Rudersdorf N;Busman TA;Mabry MH;Krivoshik AP;Humerickhouse RA;Shapiro GI;Gandhi L
通讯作者：
Gandhi L