The CREG1-FBXO27-LAMP2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes

• Published in: Experimental & molecular medicine Vol. 55; no. 9; pp. 2025 - 2038
• Main Authors: Liu, Dan, Xing, Ruinan, Zhang, Quanyu, Tian, Xiaoxiang, Qi, Yanping, Song, Haixu, Liu, Yanxia, Yu, Haibo, Zhang, Xiaolin, Jing, Quanmin, Yan, Chenghui, Han, Yaling
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2023; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13/1; 13/109; 13/89; 45/15; 631/80/39/2346; 692/699/75/230; Autophagy; Biomedical and Life Sciences; Biomedicine; Cardiac function; Cardiomyocytes; Cardiomyopathy; Diabetes; Diabetes mellitus (non-insulin dependent); F-box protein; Fibrosis; Hypertrophy; Medical Biochemistry; Molecular Medicine; Neonates; Palmitic acid; Protein expression; Proteins; Stem Cells; Transgenic mice; Western blotting; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-023-01081-2

Autophagy plays an important role in the development of diabetic cardiomyopathy. Cellular repressor of E1A-stimulated genes 1 (CREG1) is an important myocardial protective factor. The aim of this study was to investigate the effects and mechanisms of CREG1 in diabetic cardiomyopathy. Male C57BL/6 J mice, Creg1 transgenic mice and cardiac-specific knockout mice were used to establish a type 2 diabetes model. Small animal ultrasound, Masson’s staining and western blotting were used to evaluate cardiac function, myocardial fibrosis and autophagy. Neonatal mouse cardiomyocytes (NMCMs) were stimulated with palmitate, and the effects of CREG1 on NMCMs autophagy were examined. CREG1 deficiency exacerbated cardiac dysfunction, cardiac hypertrophy and fibrosis in mice with diabetic cardiomyopathy, which was accompanied by exacerbated autophagy dysfunction. CREG1 overexpression improved cardiac function and ameliorated cardiac hypertrophy and fibrosis in diabetic cardiomyopathy by improving autophagy. CREG1 protein expression was decreased in palmitate-induced NMCMs. CREG1 knockdown exacerbated cardiomyocyte hypertrophy and inhibited autophagy. CREG1 overexpression inhibited cardiomyocyte hypertrophy and improved autophagy. LAMP2 overexpression reversed the effect of CREG1 knockdown on palmitate-induced inhibition of cardiomyocyte autophagy. CREG1 inhibited LAMP2 protein degradation by inhibiting the protein expression of F-box protein 27 (FBXO27). Our findings indicate new roles of CREG1 in the development of diabetic cardiomyopathy. CREG1: A Potential Solution for Cardiac Dysfunction & Fibrosis Diabetic cardiomyopathy, a fatal complication of diabetes, can be alleviated by a protein called CREG1, according to a new study. Researchers found that CREG1 expression was reduced in the hearts of diabetic mice, and that increasing CREG1 levels improved heart function and reduced fibrosis. The protein works by promoting autophagy, a process that helps maintain cell health by breaking down damaged components. By boosting autophagy in heart cells, CREG1 could help prevent the development of diabetic cardiomyopathy. This discovery could pave the way for new therapeutic strategies to treat this debilitating condition.