RESUMEN
Myocardial ischemia/reperfusion (I/R) injury is a complex pathological process that is still not fully understood. The oxidative stress response has a critical role in the occurrence and progression of myocardial ischemia/reperfusion injury. This study investigated the specific mechanism of ubiquitin-specific protease 7 (USP7) regulation of myocardial ischemia/reperfusion injury from the perspective of proteasome degradation and its relation with the Keap1 pathway, a vital regulator of cytoprotective responses to endogenous and exogenous stress induced by reactive oxygen species (ROS) and electrophiles. Our data indicated that USP7 expression is increased during myocardial ischemia/reperfusion injury in mice, while its inhibiting suppressed the generation of oxygen free radicals and myocardial cell apoptosis, reduced myocardial tissue damage, and improved heart function. Mechanistically, USP7 stabilizes Keap1 by regulating its ubiquitination. Taken together, these findings demonstrate the potential therapeutic effect of USP7 on myocardial ischemia/reperfusion injury.
RESUMEN
The underlying mechanism of neointima formation remains unclear. Ubiquitin-specific peptidase 10 (USP10) is a deubiquitinase that plays a major role in cancer development and progression. However, the function of USP10 in arterial restenosis is unknown. Herein, USP10 expression was detected in mouse arteries and increased after carotid ligation. The inhibition of USP10 exhibited thinner neointima in the model of mouse carotid ligation. In vitro data showed that USP10 deficiency reduced proliferation and migration of rat thoracic aorta smooth muscle cells (A7r5) and human aortic smooth muscle cells (HASMCs). Mechanically, USP10 can bind to Skp2 and stabilize its protein level by removing polyubiquitin on Skp2 in the cytoplasm. The overexpression of Skp2 abrogated cell cycle arrest induced by USP10 inhibition. Overall, the current study demonstrated that USP10 is involved in vascular remodeling by directly promoting VSMC proliferation and migration via stabilization of Skp2 protein expression.
Asunto(s)
Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Neointima/metabolismo , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Línea Celular , Movimiento Celular , Proliferación Celular , Humanos , Neointima/genética , Estabilidad Proteica , Proteínas Quinasas Asociadas a Fase-S/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
The heart regeneration after apical resection and myocardial infarction in neonatal mice has been studied for years. However, the response of neonatal mouse heart under pressure overload is seldom explored. This study aimed to induce pressure overload in neonatal mice through a transverse aortic constriction (TAC) with different-gauge needles so as to investigate the effect of pressure overload on cardiomyocyte proliferation and hypertrophy in these mice. Myocardial hypertrophy was evaluated by echocardiographic, pathological, and molecular analyses. Cardiomyocyte proliferation was detected by immune-staining of phospho-histone H3, Ki67, and 5-bromo-2-deoxyuridine. Mild pressure overload induced with a 30-gauge needle stimulated cardiomyocyte proliferation, adaptive hypertrophy, and angiogenesis. The heart function was not hampered even 21 days after the surgery. Moderate pressure overload induced with a 32-gauge needle led to pathological myocardial hypertrophy, fibrosis, and heart failure 7 days after the surgery. The gene and protein expression levels of markers of hypertrophy and fibrosis increased in 32-gauge TAC group compared with that in sham and 30-gauge TAC groups. The mice barely survived after severe pressure overload induced with a 34-gauge needle. The findings of this study might provide new insights into cardiomyocyte proliferation and hypertrophy in neonatal mice under pressure overload.
