Positive feedback loop of miR-320 and CD36 regulates the hyperglycemic memory-induced diabetic diastolic cardiac dysfunction

Jiabing Zhan; Kunying Jin; Nan Ding; Yufei Zhou; Guo Hu; Shuai Yuan; Rong Xie; Zheng Wen; Chen Chen; Huaping Li; Dao Wen Wang

doi:10.1016/j.omtn.2022.12.009

Positive feedback loop of miR-320 and CD36 regulates the hyperglycemic memory-induced diabetic diastolic cardiac dysfunction

Mol Ther Nucleic Acids. 2022 Dec 14:31:122-138. doi: 10.1016/j.omtn.2022.12.009. eCollection 2023 Mar 14.

Authors

Jiabing Zhan^{1

2}, Kunying Jin^{1

2}, Nan Ding^{1

2}, Yufei Zhou^{1

2}, Guo Hu^{1

2}, Shuai Yuan^{1

2}, Rong Xie^{1

2}, Zheng Wen^{1

2}, Chen Chen^{1

2}, Huaping Li^{1

2}, Dao Wen Wang^{1

2}

Affiliations

¹ Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China.

Abstract

Intensive glycemic control is insufficient for reducing the risk of heart failure among patients with diabetes mellitus (DM). While the "hyperglycemic memory" phenomenon is well documented, little is known about its underlying mechanisms. In this study, a type 1 DM model was established in C57BL/6 mice using streptozotocin (STZ). Leptin receptor-deficient (db/db) mice were used as a model of type 2 DM. A type 9 adeno-associated virus was used to overexpress or knock down miR-320 in vivo. Diastolic dysfunction was observed in the type 1 DM mice with elevated miR-320 expression. However, glycemic control using insulin failed to reverse diastolic dysfunction. miR-320 knockdown protected against STZ-induced diastolic dysfunction. Similar results were observed in the type 2 DM mice. In vitro, we found that miR-320 promoted CD36 expression, which in turn induced further miR-320 expression. CD36 was rapidly induced by hyperglycemia at protein level compared with the much slower induction of miR-320, suggesting a positive feedback loop of CD36/miR-320 with CD36 protein induction as the initial triggering event. In conclusion, in DM-induced cardiac injury, miR-320 and CD36 mutually enhance each other's expression, leading to a positive feedback loop and a sustained hyperlipidemic state in the heart.

Keywords: CD-36; MT: Non-coding RNAs; SP1; diabetic cardiomyopathy; miR-320; positive feedback loop.