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Silencing of activin receptor-like kinase 7 alleviates aortic stiffness in type 2 diabetic rats

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Abstract

Aim

Arterial stiffness is an important feature of diabetic macrovascular complications. Activin receptor-like kinase 7 (ALK7), a member of type I transforming growth factor-β (TGF-β) receptors, is correlated with pathogenic risks of type 2 diabetes mellitus and cardiovascular diseases and may be involved in cardiovascular remodeling. We aimed to investigate whether ALK7 is implicated in diabetes-induced aortic stiffness.

Methods

Type 2 diabetes was induced by high-fat diet and low-dose streptozotocin (STZ; 27.5 mg/kg). Forty rats were separated into four groups: control, diabetes, diabetes with empty virus and diabetes treated with ALK7-shRNA. The metabolic index, ALK 7 expression and aortic stiffness were evaluated. We used gene silencing method to investigate the role of ALK7 in the pathological development.

Results

Diabetic rats showed increased blood glucose, cholesterol, triglyceride levels, severe insulin resistance and ALK7 overexpression. Diabetes enhanced aortic stiffness, as demonstrated by the loss and disruption of elastic fibers as well as by an increase in collagen fibers in the aortic media. ALK7 gene silencing ameliorated metabolic hyperlipidemia and insulin resistance. With ALK7 gene silencing, collagen content, elastin to collagen ratio, as well as collagen I-to-collagen III content ratio in diabetic rats were significantly decreased. Moreover, the phosphorylation level of Smad2/3 was markedly decreased after ALK7 gene silencing.

Conclusions

ALK7 gene silencing has a protective effect on diabetes-induced aortic stiffness, insulin resistance and hyperlipidemia, thus implicating a new potential therapeutic approach to diabetic macrovascular stiffness.

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Acknowledgments

This work was supported by the research grants from the National Basic Research Program of China (973 Program, Grant No. 2013CB530700), the National Natural Science Foundation of China (81070192, 81070141, 81100605, 81270352, 81270287, 81300168, 81471036 and 81470560), the Natural Science Foundation of Shandong Province (BS2013YY017), the Independent Innovation Foundation of Shandong University (2012JC034), the cardiovascular exploration research foundation of Chinese Medical Doctor Association (DFCMDA201320) and the Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP 20130131120065).

Conflict of interest

No potential conflicts of interest relevant to this article were reported. W.-B.L. and J.Z. researched data and wrote the manuscript; L.L. and Z.-H.W. researched data and contributed to discussion; L.H. researched data; M.Z., W.Z. and M.-X.T. wrote, reviewed and edited the manuscript; and Y.Z. reviewed and edited the manuscript.

Ethical standard

All the animal experimental protocol complied with the ethical standards of Animal Management Rules of the Chinese Ministry of Health (Document NO. 55, 2001). Ethics approval was obtained from Animal Care and Use Committee of Shandong University, China.

Informed consent disclosure

No human studies were carried out in this article.

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Authors and Affiliations

  1. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, China

    Wen-bo Li, Jing Zhao, Lu Han, Ming Zhong, Yun Zhang, Wei Zhang & Meng-xiong Tang

  2. Department of Geriatric Medicine, Qilu Hospital of Shandong University, Wenhua West Road 107, Jinan, 250012, China

    Lin Liu, Zhi-hao Wang & Meng-xiong Tang

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  1. Wen-bo Li
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Correspondence to Meng-xiong Tang.

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Managed by Antonio Secchi.

Wen-bo Li and Jing Zhao have contributed equally to the article.

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Li, Wb., Zhao, J., Liu, L. et al. Silencing of activin receptor-like kinase 7 alleviates aortic stiffness in type 2 diabetic rats. Acta Diabetol 52, 717–726 (2015). https://doi.org/10.1007/s00592-014-0706-8

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  • DOI: https://doi.org/10.1007/s00592-014-0706-8

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