Journal of the American Heart Association · 2026
Signal Recognition Granule Receptor Beta Subunit Promotes Arrhythmogenic Remodeling in the Heart Failure Mice.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zhang Jingjing, Pan Yucheng, Gong Yang, Kong Bin, Chen Tao, Shuai Wei, Huang He
Аннотация
BACKGROUND: Heart failure is a major cause of global morbidity and mortality, often complicated by ventricular arrhythmias (VAs) that worsen prognosis. The Srprb (signal recognition particle receptor beta subunit) is an endoplasmic reticulum membrane-anchored protein involved in protein processing.
METHODS: Male C57BL/6 mice received tail vein injections of adeno-associated virus to cardiac-specifically overexpress or knock down Srprb. A pressure overload-induced heart failure model was established via aortic banding 3 weeks later. Cardiac function, structural/electrical remodeling, and VA susceptibility were evaluated 4 weeks post aortic banding using echocardiography, ECG, in vivo electrophysiology, and molecular/pathological analyses. In vitro, primary neonatal mouse cardiomyocytes and fibroblasts were transfected with Srprb-modulating adenoviruses to investigate its role in hypertrophy and fibrosis. Pathway inhibitors were used to confirm mechanisms.
RESULTS: Srprb knockdown improved pressure overload-induced cardiac structural and electrical remodeling, reducing VAs. Conversely, Srprb overexpression exacerbated these abnormalities and increased VA incidence. In vitro, Srprb knockdown alleviated angiotensin II-induced cardiomyocyte hypertrophy and TGF-β (transforming growth factor-β)-induced fibroblast fibrosis, whereas its overexpression aggravated them. Mechanistically, Srprb promoted VA vulnerability by activating endoplasmic reticulum stress and the TLR4/CaMKII/NF-κB (Toll-like receptor 4/Ca2+/calmodulin-dependent protein kinase II/nuclear factor kappa B) signaling pathway.
CONCLUSIONS: Srprb knockdown improved ventricular remodeling and suppressed VAs in mice with heart failure, whereas its overexpression has opposite effects. These actions were mediated through regulation of endoplasmic reticulum stress and the TLR4/CaMKII/NF-κB pathway.
METHODS: Male C57BL/6 mice received tail vein injections of adeno-associated virus to cardiac-specifically overexpress or knock down Srprb. A pressure overload-induced heart failure model was established via aortic banding 3 weeks later. Cardiac function, structural/electrical remodeling, and VA susceptibility were evaluated 4 weeks post aortic banding using echocardiography, ECG, in vivo electrophysiology, and molecular/pathological analyses. In vitro, primary neonatal mouse cardiomyocytes and fibroblasts were transfected with Srprb-modulating adenoviruses to investigate its role in hypertrophy and fibrosis. Pathway inhibitors were used to confirm mechanisms.
RESULTS: Srprb knockdown improved pressure overload-induced cardiac structural and electrical remodeling, reducing VAs. Conversely, Srprb overexpression exacerbated these abnormalities and increased VA incidence. In vitro, Srprb knockdown alleviated angiotensin II-induced cardiomyocyte hypertrophy and TGF-β (transforming growth factor-β)-induced fibroblast fibrosis, whereas its overexpression aggravated them. Mechanistically, Srprb promoted VA vulnerability by activating endoplasmic reticulum stress and the TLR4/CaMKII/NF-κB (Toll-like receptor 4/Ca2+/calmodulin-dependent protein kinase II/nuclear factor kappa B) signaling pathway.
CONCLUSIONS: Srprb knockdown improved ventricular remodeling and suppressed VAs in mice with heart failure, whereas its overexpression has opposite effects. These actions were mediated through regulation of endoplasmic reticulum stress and the TLR4/CaMKII/NF-κB pathway.