Longming Huang, Kai Luo, Xinjie Zhang, Guowei Zeng, Bo Chen, Cong Li, Xiaoyang Zhang, Haoyu Li, Mengyi Zhang, Wenjun Zhou, Jinwen Pang, Jinghao Zheng, Bozhong Shi, Xiaomin He
This study introduces a novel model of pediatric LV reverse remodeling in male mice, delineating the trajectory and transcriptional footprints during the reverse remodeling process. The Mitophagy-mtDNA-cGAS-STING axis plays a vital role and holds therapeutic potential to promote young heart recovery.
BACKGROUND: Left ventricular (LV) reverse remodeling has been linked to long-term prognosis and life quality of pediatric patients with LV outflow tract obstruction. However, a lack of suitable animal model limits further study of LV reverse remodeling in young hearts. This study reports on the development and mechanism exploration of an animal model mimicking pediatric LV reverse remodeling.
METHODS: A reversible neonatal ascending aorta constriction mice model using absorbable suture was established to simulate pediatric LV reverse remodeling. Cardiac hypertrophy, myocardial fibrosis, angiogenesis, exercise tolerance, and myocardial reserve throughout the reverse remodeling process were evaluated. Multiple-time points RNA sequencing identified key genes and pathways involved. Cardiomyocyte-specific stimulator of interferon genes (STING) knockout mice were generated for mechanism study.
RESULTS: In the reversible neonatal ascending aorta constriction model, hydrolysis of the absorbable suture reduced cardiac afterload after ventricular remodeling, initiating reverse remodeling at 4 weeks postsurgery. Reverse remodeling young hearts displayed improved function, resolution of fibrosis, but persistent hypertrophy, reduced exercise capacity, and myocardial reserve. Multiple-time points RNA sequencing and in vivo experiments revealed a gradual upregulation of mitophagy during reverse remodeling, along with suppression of the mitochondrial DNA (mtDNA)-cyclic GMP-AMP synthase (cGAS) in which the STING gene is flanked by loxP sites-STING pathway. Cardiomyocyte-specific STING knockout enhanced early reverse remodeling. The early application of urolithin A promoted mitophagy and suppressed the mtDNA-cGAS-STING pathway, accelerating reverse remodeling.
CONCLUSIONS: This study introduces a novel model of pediatric LV reverse remodeling in male mice, delineating the trajectory and transcriptional footprints during the reverse remodeling process. The Mitophagy-mtDNA-cGAS-STING axis plays a vital role and holds therapeutic potential to promote young heart recovery.