Long-term Elevation Of Cardiomyocyte Protein O-GlcNAc Levels Induces Cardiac Hypertrophy And Reduced Mitochondrial Function With Preserved Systolic Contractility
CIRCULATION RESEARCH(2023)
摘要
The severity and development of cardiovascular disease (CVD) can be affected by lifestyle and metabolic diseases, which can impact various mechanisms, including post-translational modifications (PTM). A specific PTM, known as protein O-linked β-N acetylglucosamine modification (O-GlcNAc), has been linked to both physiological responses and pathological progression of heart failure. This study was aimed to test whether sustained cardiac protein O-GlcNAc of proteins in cardiomyocytes contributes to cardiac adaptations or is sufficient to progress toward pathophysiology. Specifically, we generated transgenic mice overexpressing a naturally occurring dominant-negative O-GlcNAcase (dnOGA) in an inducible and cardiomyocyte-specific manner (dnOGAh). We induced dnOGA in male and female 8-10-weeks-old mice and examined the effects of 2-weeks (2wk) and 24-weeks (24wk) dnOGA overexpression, which resulted in a 1.8-fold increase in protein O - GlcNAc levels ( P <0.01). The results showed that a 2wk increase in protein O-GlcNAc levels did not impact heart weight or function; however, 24wk of elevated protein O-GlcNAc led to cardiac hypertrophy (+19.8%, P <0.01), fibrosis (M. Trichrome; +578%, P <0.005), and diastolic dysfunction (E/A; +314%, P <0.001). Despite several changes in gene expression associated with CVD, systolic function was maintained in 24wk dnOGA overexpression. mRNA-seq analysis revealed several gene signatures changed as early as 2wk of dnOGA that progressed at 24wk, including reduction of mitochondrial oxidative phosphorylation, fatty acid and glucose metabolism pathways (
更多查看译文
关键词
Cardiac hypertrophy,Remodeling,Cardiac metabolism
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要