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miR-448-3p alleviates diabetic vascular dysfunction by inhibiting endothelial-mesenchymal transition through DPP-4
Guo-Ying Guan1, Nan Wei1, Tao Song1
1Department of Geriatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Abstract:
Diabetes mellitus (DM) often causes vascular endothelial damage and alters vascular microRNA (miR) expression. miR-448-3p has been reported to be involved in the development of DM, but whether miR-448-3p regulates diabetic vascular endothelial dysfunction remains unclear. To investigate the molecular mechanism of diabetic vascular endothelial dysfunction and the role of miR-448-3p therein, Sprague-Dawley rats were injected with streptozotocin (STZ) to establish diabetic animal model and the rat aortic endothelial cells were treated with high glucose to establish diabetic cell model. For the treatment group, after the induction of diabetes, the miR-448-3p levels in vivo and in vitro were upregulated by adeno-associated virus serotype 2 (AAV2)-miR-448-3p injection and miR-448-3p mimic transfection, respectively. Our results showed that AAV2-miR-448-3p injection alleviated the body weight loss and blood glucose level elevation induced by STZ injection. The miR-448-3p level was significantly decreased and the dipeptidyl peptidase-4 (DPP-4) messenger RNA level was increased in diabetic animal and cell models, which was reversed by miR-448-3p treatment. Moreover, the diabetic rats exhibited endothelial damage and endothelial-mesenchymal transition (EndMT), while AAV2-miR-448-3p injection relieved those situations. In vitro experiments demonstrated that miR-448-3p overexpression in endothelial cells alleviated endothelial damage by inhibiting EndMT through blocking the transforming growth factor-β/Smad pathway. We further proved that miR-448-3p negatively regulated DPP-4 by binding to its 3'-untranslated region, and DPP-4 overexpression reversed the effect of miR-448-3p overexpression on EndMT. Overall, we conclude that miR-448-3p overexpression inhibits EndMT via targeting DPP-4 and further ameliorates diabetic vascular endothelial dysfunction, indicating that miR-448-3p may serve as a promising therapeutic target for diabetic endothelial dysfunction.
Insights
MicroRNA-448-3p upregulation ameliorates diabetic vascular endothelial dysfunction by inhibiting endothelial-mesenchymal transition via targeting dipeptidyl peptidase-4. This suggests miR-448-3p as a potential therapeutic target for diabetes complications.
Area of Science:
- Endocrinology
- Molecular Biology
- Vascular Biology
Background:
- Diabetes mellitus (DM) is associated with vascular endothelial damage and altered microRNA (miR) expression.
- The role of miR-448-3p in diabetic vascular endothelial dysfunction is not fully understood.
- Investigating miR-448-3p's mechanism is crucial for understanding and treating diabetic vascular complications.
Purpose of the Study:
- To elucidate the molecular mechanism of diabetic vascular endothelial dysfunction.
- To determine the specific role of miR-448-3p in this process.
- To evaluate miR-448-3p as a potential therapeutic target for diabetic vascular complications.
Main Methods:
- Established diabetic rat and rat aortic endothelial cell models using streptozotocin and high glucose, respectively.
- Upregulated miR-448-3p levels in vivo using adeno-associated virus serotype 2 (AAV2)-miR-448-3p and in vitro using miR-448-3p mimic transfection.
- Assessed endothelial damage, endothelial-mesenchymal transition (EndMT), and the transforming growth factor-β/Smad pathway; identified dipeptidyl peptidase-4 (DPP-4) as a target of miR-448-3p.
Main Results:
- miR-448-3p upregulation alleviated hyperglycemia and body weight loss in diabetic rats.
- Overexpression of miR-448-3p inhibited EndMT and endothelial damage in diabetic models.
- miR-448-3p directly targeted DPP-4 mRNA, and DPP-4 overexpression reversed miR-448-3p's protective effects on EndMT.
Conclusions:
- miR-448-3p overexpression ameliorates diabetic vascular endothelial dysfunction by inhibiting EndMT.
- This protective effect is mediated through the inhibition of the transforming growth factor-β/Smad pathway and targeting of DPP-4.
- miR-448-3p represents a promising therapeutic target for diabetic vascular endothelial dysfunction.
