In Mice Subjected to Chronic Stress, Exogenous cBIN1 Preserves Calcium-Handling Machinery and Cardiac Function

Liu, Yan; Zhou, Kaiwen; Li, Jing; Agvanian, Sosse; Caldaruse, Ana-Maria; Shaw, Seiji; Hitzeman, Tara C.; Shaw, Robin M.; Hong, TingTing

doi:10.1016/j.jacbts.2020.03.006

Cited by 28 publications

(55 citation statements)

References 43 publications

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“…We recently reported that, in mice receiving AAV9-cBIN1 pretreatment (3 × 10 10 vg at 3 weeks prior to TAC surgery; Figure 6A), the incidence of TAC-induced HF is significantly reduced with a resultant better HF-free survival at 8 weeks post-TAC (Liu et al, 2020). These data are consistent with the observed myocardial protection when AAV9 was administered after TAC surgery.…”

Section: Resultssupporting

confidence: 83%

“…There are currently several completed or ongoing clinical trials of HF gene therapies targeting various pathways such as the β-adrenergic system, Ca 2+ cycling proteins, and cell death pathways, as well as homing stem cells (Tilemann et al, 2012). We recently found that targeting the calcium regulating microdomains at t-tubules can be effectively achieved by transducing the essential microdomain-organizing protein cBIN1 (Liu et al, 2020). By stabilizing t-tubule microdomains, cBIN1 preserves cytosolic calcium homeostasis and contributes to increasing systolic calcium release, improving diastolic reuptake, limiting SR leak for electrical stability maintenance, and preserving mitochondrial function to limit mitochondrial-associated cell death.…”

Section: Discussionmentioning

confidence: 99%

“…For rescue experiments, at 5 weeks post the onset of TAC, mice received retro-orbital injection of 100 μl of 3 × 10 10 vector genome (vg) of AAV9 virus (Welgen, Inc.) transducing cBIN1-V5 or GFP-V5 (Basheer et al, 2017). In the prevention experiments where cBIN1-V5 was reported to provide protection of mouse hearts against subsequent TAC-induced HF (Liu et al, 2020), mice received the same dose (3 × 10 10 vg) of AAV9 virus transducing cBIN1-V5 and GFP-V5 3 weeks before TAC surgery was done.…”

Section: Animal Model Designmentioning

confidence: 99%

“…In humans, plasma CS (cBIN1 score) is an index of myocyte cBIN1 level, which identifies myocardial structural remodeling, facilitating HF diagnosis and prognosis (Nikolova et al, 2018). In mouse hearts subjected to chronic stress, pretreatment with exogenous cBIN1 preserves the microdomain-organized distribution of Cav1.2 and SERCA2a, maintaining normal inotropy and lusitropy (Liu et al, 2020). These data indicate that cBIN1 replacement can be an effective HF therapy with the potential to recover myocardial function in hearts with preexisting HF.…”

Section: Introductionmentioning

confidence: 95%

“…Since increased afterload is an important primary and secondary cause of HF (Blaufarb and Sonnenblick, 1996), our current study uses a mouse model of elevated afterload induced by transverse-aortic constriction (TAC). In TAC mice, we recently reported that cBIN1 pretreatment prevents HF development (Liu et al, 2020). Here, we used adeno-associated virus 9 (AAV9)-mediated gene transfer to introduce exogenous cBIN1 in post-TAC mouse hearts with pre-existing HF.…”

Section: Introductionmentioning

confidence: 99%

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Exogenous Cardiac Bridging Integrator 1 Benefits Mouse Hearts With Pre-existing Pressure Overload-Induced Heart Failure

Agvanian

Zhou

et al. 2020

Front. Physiol.

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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 × 10 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. 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.

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Section: Resultssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Animal Model Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Exogenous Cardiac Bridging Integrator 1 Benefits Mouse Hearts With Pre-existing Pressure Overload-Induced Heart Failure

Agvanian

Zhou

et al. 2020

Front. Physiol.

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Bmi‐1‐RING1B prevents GATA4‐dependent senescence‐associated pathological cardiac hypertrophy by promoting autophagic degradation of GATA4

Chen

Zhou

Chen

et al. 2022

Clinical & Translational Med

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Aims Senescence‐associated pathological cardiac hypertrophy (SA‐PCH) is associated with upregulation of foetal genes, fibrosis, senescence‐associated secretory phenotype (SASP), cardiac dysfunction and increased morbidity and mortality. Therefore, we conducted experiments to investigate whether GATA4 accumulation induces SA‐PCH, and whether Bmi‐1‐RING1B promotes GATA4 ubiquitination and its selective autophagic degradation to prevent SA‐PCH. Methods and results Bmi‐1 ‐deficient ( Bmi‐1 −/− ), transgenic Bmi‐1 overexpressing ( Bmi‐1 Tg ) and wild‐type (WT) mice were infused with angiotensin II (Ang II) to stimulate the development of SA‐PCH. Through bioinformatics analysis with RNA sequencing data from cardiac tissues, we found that Bmi‐1‐RING1B and autophagy are negatively related to SA‐PCH. Bmi‐1 deficiency promoted GATA4‐dependent SA‐PCH by increasing GATA4 protein and hypertrophy‐related molecules transcribed by GATA4 such as ANP and BNP. Bmi‐1 deficiency stimulated NF‐κB‐p65‐dependent SASP, leading to cardiac dysfunction, cardiomyocyte hypertrophy and senescence. Bmi‐1 overexpression repressed GATA4‐dependent SA‐PCH. GATA4 degraded by Bmi‐1 was mainly dependent on autophagy rather than proteasome. In human myocardium, p16 positively correlated with ANP and GATA4 and negatively correlated with LC3B, Bmi‐1 and RING1B; GATA4 positively correlated with p62 and negatively correlated with Bmi‐1 and LC3B. With increased p16 protein levels, ANP‐, BNP‐ and GATA4‐positive cells or areas increased; however, LC3B‐positive cells or areas decreased in human myocardium. GATA4 is ubiquitinated after combining with Bmi‐1‐RING1B, which is then recognised by p62, is translocated to autophagosomes to form autophagolysosomes and degraded. Downregulated GATA4 ameliorated SA‐PCH and cardiac dysfunction by reducing GATA4‐dependent hypertrophy and SASP‐related molecules. Bmi‐1 combined with RING1B (residues 1–179) and C‐terminus of GATA4 (residues 206–443 including zinc finger domains) through residues 1–95, including a RING‐HC‐finger. RING1B combined with C‐terminus of GATA4 through the C‐terminus (residues 180–336). Adeno‐associated viral vector serotype 9 (AAV9)‐ cytomegalovirus (CMV)‐Bmi‐1‐RING1B treatment significantly attenuated GATA4‐dependent SA‐PCH through promoting GATA4 autophagic degradation. Conclusions Bmi‐1‐RING1B maintained cardiac function and prevented SA‐PCH by promoting selective autophagy for degrading GATA4. Translational perspective AAV9‐ CMV ‐ Bmi‐1 ‐ RING1B could be used for translational gene therapy to ubiquitinate GATA4 and prevent GATA4‐dependent SA‐PCH. Also, the com...

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Calcium-Dependent Signaling in Cardiac Myocytes

Ko¹,

Smith²,

Grandi³

2022

Cardiovascular Signaling in Health and Disease

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In Mice Subjected to Chronic Stress, Exogenous cBIN1 Preserves Calcium-Handling Machinery and Cardiac Function

Cited by 28 publications

References 43 publications

Exogenous Cardiac Bridging Integrator 1 Benefits Mouse Hearts With Pre-existing Pressure Overload-Induced Heart Failure

Exogenous Cardiac Bridging Integrator 1 Benefits Mouse Hearts With Pre-existing Pressure Overload-Induced Heart Failure

Bmi‐1‐RING1B prevents GATA4‐dependent senescence‐associated pathological cardiac hypertrophy by promoting autophagic degradation of GATA4

Calcium-Dependent Signaling in Cardiac Myocytes

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