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FP-receptor gene silencing ameliorates myocardial fibrosis and protects from diabetic cardiomyopathy

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Abstract

Prostaglandin F2α-F-prostanoid (PGF2α-FP) receptor is closely related to insulin resistance, which plays a causal role in the pathogenesis of diabetic cardiomyopathy (DCM). We sought to reveal whether PGF2α-FP receptor plays an important part in modulating DCM and the mechanisms involved. We established the type 2 diabetes rat model by high-fat diet and low-dose streptozotocin (STZ) and then evaluated its characteristics by metabolite tests, Western blot analysis for FP-receptor expression, histopathologic analyses of cardiomyocyte density and fibrosis area. Next, we used gene silencing to investigate the role of FP receptor in the pathophysiologic features of DCM. Our study showed elevated cholesterol, triglyceride, glucose, and insulin levels, severe insulin resistance, and FP-receptor overexpression in diabetic rats. The collagen volume fraction (CVF) and perivascular collagen area/luminal area (PVCA/LA) were higher in the diabetic group than the control group (CVF% 10.99 ± 0.99 vs 1.59 ± 0.18, P < 0.05; PVCA/LA% 17.07 ± 2.61 vs 2.86 ± 0.69, P < 0.05). We found that the silencing of FP receptor decreased cholesterol, triglyceride, glucose, and insulin levels and ameliorated insulin resistance. The CVF and PVCF/LA were significantly downregulated in FP-receptor short hairpin RNA (shRNA) treatment group (FP-receptor shRNA group vs vehicle group: CVF% 5.59 ± 0.92 vs 10.97 ± 1.33, P < 0.05, PVCA/LA% 4.74 ± 1.57 vs 14.79 ± 2.22, P < 0.05; FP-receptor shRNA + PGF2α group vs vehicle group : CVF% 5.19 ± 0.79 vs 10.97 ± 1.33, P < 0.05, PVCA/LA% 5.96 ± 1.15 vs 14.79 ± 2.22, P < 0.05, respectively). Furthermore, with FP-receptor gene silencing, the activated protein kinase C (PKC) and Rho kinase were significantly decreased, and the blunted phosphorylation of Akt was restored. FP-receptor gene silencing may exert a protective effect on DCM by improving myocardial fibrosis, suggesting a new therapeutic approach for human DCM.

Key messages

  • FP-receptor gene silencing improves glucose tolerance and insulin resistance in type 2 diabetes (T2D).

  • FP-receptor gene silencing modulates the activities of PKC/Rho and Akt signaling pathways in T2D.

  • FP-receptor gene silencing decreases collagen expression and ameliorates myocardial fibrosis in T2D.

  • FP-receptor gene silencing protects from diabetic cardiomyopathy in T2D.

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Acknowledgments

This work was supported by the research grants from the Independent Innovation Foundation of Shandong University (nos. 2012JC034), the Key Technologies Research and Development Program of Shandong Province (nos. 2010G0020262), the Natural Science Foundation of Shandong Province (nos. ZR2009CM022), the National Natural Science Foundation of China (nos. 30871038, 30971215, 81070192, 81070141, 81100605, 81270287, and 81270352), and the National Basic Research Program of China (973 Program, no. 2012CB722406).

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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, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China

    Wen-yuan Ding, Lin Liu, Zhi-hao Wang, Meng-xiong Tang, Yun Ti, Lu Han, Lei Zhang, Yun Zhang, Ming Zhong & Wei Zhang

  2. Department of Cardiology, Qilu Hospital of Shandong University, No.107 Wenhua West Road, Jinan, 250012, People’s Republic of China

    Wen-yuan Ding, Lin Liu, Yun Ti, Lu Han, Lei Zhang, Yun Zhang, Ming Zhong & Wei Zhang

  3. Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China

    Zhi-hao Wang

  4. Department of Emergency, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China

    Meng-xiong Tang

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  1. Wen-yuan Ding
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  2. Lin Liu
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  8. Yun Zhang
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  9. Ming Zhong
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  10. Wei Zhang
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Correspondence to Ming Zhong or Wei Zhang.

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Ding, Wy., Liu, L., Wang, Zh. et al. FP-receptor gene silencing ameliorates myocardial fibrosis and protects from diabetic cardiomyopathy. J Mol Med 92, 629–640 (2014). https://doi.org/10.1007/s00109-013-1119-9

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  • DOI: https://doi.org/10.1007/s00109-013-1119-9

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