Abstract
Background: 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.Methods: 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 × 1010 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.Results: 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).Conclusions: In mice with pre-existing HF, exogenous cBIN1 can normalize t-tubule calcium handling microdomains, limit HF progression, rescue cardiac function, and improve survival.
Highlights
Heart failure (HF) is the fastest growing cardiovascular disorder affecting over 20 million people worldwide and 6.2 million Americans (Roger, 2013; Virani et al, 2020)
In mice with pre-existing HF, exogenous Cardiac bridging integrator 1 (cBIN1) can normalize t-tubule calcium handling microdomains, limit HF progression, rescue cardiac function, and improve survival
To explore whether targeting cBIN1-microdomain can be a new therapy for HF, we investigated how cardiac cBIN1 affects HF development in mice subjected to pressure overload stress
Summary
Heart failure (HF) is the fastest growing cardiovascular disorder affecting over 20 million people worldwide and 6.2 million Americans (Roger, 2013; Virani et al, 2020). During HF development, the pathophysiologic cellular hallmark of failing ventricular myocytes is abnormal calcium transients with impaired intracellular calcium homeostasis (Gomez et al, 1997, 2001; Litwin et al, 2000; Louch et al, 2004), which disrupts excitation-contraction (EC) coupling (Perreault et al, 1992), impairs electrical stability (Landstrom et al, 2017), and disturbs mitochondrial metabolism (LopezCrisosto et al, 2017). Calcium homeostasis is critical in maintaining normal cardiac pump function, electrical stability, and metabolism. Disturbed beat-to-beat calcium dynamic, as occurs in diseased hearts, will lead to pump failure, lethal arrhythmias, and severe metabolic disorder. We aim to explore whether cBIN1 replacement therapy can improve myocardial function in continuously stressed hearts with pre-existing HF
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