Key result
Sirt6 knockdown worsens diabetic cardiomyopathy and exacerbates endothelial-to-mesenchymal transition via enhanced Notch1 activation.
Why the study?
EndMT directly affects cardiac function in DCM through unknown mechanisms, prompting investigation into whether Sirt6 participates in EndMT during T2DM development.
Sirt6 protects against diabetic cardiomyopathy by inhibiting endothelial-to-mesenchymal transition via the Notch1 signaling pathway, suggesting a potential therapeutic target.
Answers are grounded in this paper and cite their sources.
Sirt6-Notch1 modulation identified in diabetic cardiomyopathy models; hypothesis-generating and requires human validation before any clinical consideration.
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: ) 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: 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.
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Zhang et al. (2020) studied Diabetic cardiomyopathy. Sirt6 knockdown vs. Control was evaluated on Cardiac function and endothelial-to-mesenchymal transition. Sirt6 knockdown worsened diabetic cardiomyopathy and exacerbated endothelial-to-mesenchymal transition in cardiac microvascular endothelial cells via enhanced Notch1 activation.
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