Li Jing, Agvanian Sosse, Zhou Kang, Shaw Robin M, Hong TingTing
Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United States.
Front Physiol. 2020 Jun 24;11:708. doi: 10.3389/fphys.2020.00708. eCollection 2020.
: Cardiac bridging integrator 1 (cBIN1) organizes transverse tubule (t-tubule) membrane calcium handling microdomains required for normal beat-to-beat contractility. cBIN1 is transcriptionally reduced in heart failure (HF). We recently found that cBIN1 pretreatment can limit HF development in stressed mice. Here, we aim to explore whether cBIN1 replacement therapy can improve myocardial function in continuously stressed hearts with pre-existing HF. : Adult male mice were subjected to sham or transverse aortic constriction (TAC) surgery at the age of 8-10 weeks old. Adeno-associated virus 9 (AAV9) transducing cBIN1-V5 or GFP-V5 (3 × 10 vg) was administered through retro-orbital injection at 5 weeks post-TAC. Mice were followed by echocardiography to monitor cardiac function until 20 weeks after TAC. Overall survival, heart and lung weight (LW), and HF incidence were determined. In a second set of animals in which AAV9-cBIN1 pretreatment prevents HF, we recorded cardiac pressure-volume (PV) loops and obtained myocardial immunofluorescence imaging. : The overall Kaplan-Meir survival of AAV9-cBIN1 mice was 77.8%, indicating a significant partial rescue between AAV9-GFP (58.8%) and sham (100%) treated mice. In mice with ejection fraction (EF) ≥30% prior to AAV9 injection at 5 weeks post-TAC, AAV9-cBIN1 significantly increased survival to 93.3%, compared to 62.5% survival for AAV9-GFP treated mice. The effect of exogenous cBIN1 was to attenuate TAC-induced left ventricular (LV) dilation and prevent further HF development. Recovery of EF also occurs in AAV9-cBIN1-treated mice. We found that EF increases to a peak at 6-8 weeks post-viral injection. Furthermore, PV loop analysis identified that AAV9-cBIN1 increases both systolic and diastolic function of the post-TAC hearts. At the myocyte level, AAV9-cBIN1 normalizes cBIN1 expression, t-tubule membrane intensity, and intracellular distribution of Cav1.2 and ryanodine receptors (RyRs). : In mice with pre-existing HF, exogenous cBIN1 can normalize t-tubule calcium handling microdomains, limit HF progression, rescue cardiac function, and improve survival.
心脏桥联整合蛋白1（cBIN1）组织正常逐搏收缩性所需的横管（T管）膜钙处理微区。cBIN1在心力衰竭（HF）中表达转录下调。我们最近发现，cBIN1预处理可限制应激小鼠HF的发展。在此，我们旨在探讨cBIN1替代疗法是否能改善已有HF的持续应激心脏的心肌功能。：8至10周龄的成年雄性小鼠接受假手术或主动脉缩窄（TAC）手术。在TAC术后5周通过眶后注射给予转导cBIN1-V5或GFP-V5（3×10 vg）的腺相关病毒9（AAV9）。对小鼠进行超声心动图监测心脏功能，直至TAC术后20周。测定总体生存率、心脏和肺重量（LW）以及HF发病率。在第二组AAV9-cBIN1预处理可预防HF的动物中，我们记录了心脏压力-容积（PV）环并获得心肌免疫荧光成像。：AAV9-cBIN1小鼠的总体Kaplan-Meir生存率为77.8%，表明在AAV9-GFP（58.8%）和假手术（100%）处理的小鼠之间有显著的部分挽救作用。在TAC术后5周AAV9注射前射血分数（EF）≥30%的小鼠中，AAV9-cBIN1显著提高生存率至93.3%，而AAV9-GFP处理的小鼠生存率为62.5%。外源性cBIN1的作用是减轻TAC诱导的左心室（LV）扩张并防止HF进一步发展。AAV9-cBIN1处理的小鼠中EF也会恢复。我们发现EF在病毒注射后6至8周达到峰值。此外，PV环分析表明AAV9-cBIN1可增加TAC术后心脏的收缩和舒张功能。在心肌细胞水平，AAV9-cBIN1使cBIN1表达、T管膜强度以及Cav1.2和兰尼碱受体（RyRs）的细胞内分布正常化。：在已有HF的小鼠中，外源性cBIN1可使T管钙处理微区正常化，限制HF进展，挽救心脏功能并提高生存率。
