Ye Liu1, Yikun Zhu1, Sujun Liu1, Jiong Liu2, Xing Li3. 1. Department of Endocrinology, The Second Hospital of ShanXi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China. 2. Department of Nuclear Medicine, The Second Hospital of ShanXi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China. 3. Department of Endocrinology, The Second Hospital of ShanXi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China. xingl0220@163.com.
Abstract
OBJECTIVE: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes, but its pathogenesis is still unclear. This study investigated the mechanism of long noncoding RNA (lncRNA) NORAD in DCM. METHODS: Male leptin receptor-deficient (db/db) mice and leptin control mice (db/ +) were procured. DCM model was established by subcutaneous injection of angiotensin II (ATII) in db/db mice. NORAD lentivirus shRNA or Adv-miR-125a-3p was administered to analyze cardiac function, fibrosis, serum biochemical indexes, inflammation and fibrosis. Primary cardiomyocytes were extracted and transfected with miR-125a-3p mimic. The competing endogenous RNA (ceRNA) network of NORAD/miR-125a-3p/Fyn was verified. The levels of fibrosis- and inflammation-related factors were measured. RESULTS: In db/db mice treated with ATII, the body weight and serum biochemical indexes were increased, while the cardiac function was decreased, and inflammatory cell infiltration and fibrosis were induced. NORAD was upregulated in diabetic and DCM mice. The 4-week intravenous injection of NORAD lentivirus shRNA reduced body weight and serum biochemical indexes, improved cardiac function, and attenuated inflammation and fibrosis in DCM mice. NORAD acted as a sponge to adsorb miR-125a-3p, and miR-125a-3p targeted Fyn. Intravenous injection of miR-125a-3p adenovirus improved cardiac function and fibrosis and reduced inflammatory responses in DCM mice. Co-overexpression of miR-125-3p and Fyn partly reversed the improving effect of miR-125-3p overexpression on cardiac fibrosis in DCM mice. CONCLUSION: NORAD lentivirus shRNA improved cardiac function and fibrosis and reduced inflammatory responses in DCM mice via the ceRNA network of NORAD/miR-125a-3p/Fyn. These findings provide a valuable and promising therapeutic target for the treatment of DCM.
OBJECTIVE: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes, but its pathogenesis is still unclear. This study investigated the mechanism of long noncoding RNA (lncRNA) NORAD in DCM. METHODS: Male leptin receptor-deficient (db/db) mice and leptin control mice (db/ +) were procured. DCM model was established by subcutaneous injection of angiotensin II (ATII) in db/db mice. NORAD lentivirus shRNA or Adv-miR-125a-3p was administered to analyze cardiac function, fibrosis, serum biochemical indexes, inflammation and fibrosis. Primary cardiomyocytes were extracted and transfected with miR-125a-3p mimic. The competing endogenous RNA (ceRNA) network of NORAD/miR-125a-3p/Fyn was verified. The levels of fibrosis- and inflammation-related factors were measured. RESULTS: In db/db mice treated with ATII, the body weight and serum biochemical indexes were increased, while the cardiac function was decreased, and inflammatory cell infiltration and fibrosis were induced. NORAD was upregulated in diabetic and DCM mice. The 4-week intravenous injection of NORAD lentivirus shRNA reduced body weight and serum biochemical indexes, improved cardiac function, and attenuated inflammation and fibrosis in DCM mice. NORAD acted as a sponge to adsorb miR-125a-3p, and miR-125a-3p targeted Fyn. Intravenous injection of miR-125a-3p adenovirus improved cardiac function and fibrosis and reduced inflammatory responses in DCM mice. Co-overexpression of miR-125-3p and Fyn partly reversed the improving effect of miR-125-3p overexpression on cardiac fibrosis in DCM mice. CONCLUSION: NORAD lentivirus shRNA improved cardiac function and fibrosis and reduced inflammatory responses in DCM mice via the ceRNA network of NORAD/miR-125a-3p/Fyn. These findings provide a valuable and promising therapeutic target for the treatment of DCM.