Sirt6-Mediated Endothelial-to-Mesenchymal Transition Contributes Toward Diabetic Cardiomyopathy via the Notch1 Signaling Pathway

Yan Zhang; Yuan Dong; Zhenyu Xiong; Zhengru Zhu; Fanya Gao; Tingting Wang; Wanrong Man; Dong Sun; Jie Lin; Tongbin Li; Congye Li; Zhijing Zhao; Min Shen; Dongdong Sun; Yanhong Fan

doi:10.2147/DMSO.S287287

Sirt6-Mediated Endothelial-to-Mesenchymal Transition Contributes Toward Diabetic Cardiomyopathy via the Notch1 Signaling Pathway

Diabetes Metab Syndr Obes. 2020 Dec 7:13:4801-4808. doi: 10.2147/DMSO.S287287. eCollection 2020.

Authors

Yan Zhang^#¹, Yuan Dong^#¹, Zhenyu Xiong^#¹, Zhengru Zhu², Fanya Gao³, Tingting Wang¹, Wanrong Man¹, Dong Sun¹, Jie Lin¹, Tongbin Li¹, Congye Li¹, Zhijing Zhao¹, Min Shen¹, Dongdong Sun¹, Yanhong Fan¹

Affiliations

¹ Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
² Department of Otolaryngology Head and Neck Surgery, First Hospital of Lanzhou University, Lanzhou, People's Republic of China.
³ Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an Medical University, Xi'an, People's Republic of China.

^# Contributed equally.

Abstract

Background: Endothelial-to-mesenchymal transition (EndMT) is an important source of myofibroblasts that directly affects cardiac function in diabetic cardiomyopathy (DCM) via an unknown underlying mechanism. Sirt6 is a member of the Sirtuin family of NAD(+)-dependent enzymes that plays an important role in glucose and fatty acid metabolism. In this study, we investigated whether Sirt6 participates in EndMT during the development of T2DM and the possible underlying regulatory mechanisms.

Methods: Endothelium-specific Sirt6 knockout (Sirt6-KO^EC) mice (C57BL/6 genetic background) were generated using the classic Cre/loxp gene recombination system. T2DM was induced in eight-week-old male mice by feeding with a high-fat diet for three weeks followed by i.p. injection with 30 mg/kg of streptozotocin. The weight, lipids profiles, insulin, food intake and water intake of experimental animals were measured on a weekly basis. Cardiac microvascular endothelial cells (CMECs) were obtained from adult male mice; the isolated cells were cultured with high glucose (HG; 33 mmol/L) and palmitic acid (PA; 500 μmol/L) in DMEM for 24 h, or with normal glucose (NG; 5 mmol/L) as the control.

Results: Sirt6 expression is significantly downregulated in CMECs treated with HG+PA. Additionally, Sirt6-KO^EC was found to worsen DCM, as indicated by aggravated perivascular fibrosis, cardiomyocyte hypertrophy, and decreased cardiac function. In vitro, Sirt6 knockdown exacerbated the proliferation, and migration of CMECs exposed to HG+PA. Mechanistically, Sirt6 knockdown significantly enhanced Notch1 activation in CMECs treated with HG+PA, whereas Notch1 adenoviral interference significantly blunted the effects of Sirt6 knockdown on CMECs.

Conclusion: This study is the first to demonstrate that Sirt6 participates in EndMT via the Notch1 signaling pathway in CMECs stimulated with HG+PA. Therefore, the findings of this study suggest that Sirt6 could provide a potential treatment strategy for DCM.

Keywords: Sirt6; cardiac function; diabetic cardiomyopathy; endothelial-to-mesenchymal transition; fibrosis.