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Cilostazol Promotes Angiogenesis and Increases Cell Proliferation After Myocardial Ischemia–Reperfusion Injury Through a cAMP-Dependent Mechanism

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Abstract

Purpose

Previous study indicated the protective role of cilostazol in ischemia–reperfusion (I/R) injury. Here, we aimed to explore the function of cilostazol in myocardial I/R injury and the underlying mechanism.

Methods

The myocardial I/R injury rat model was constructed, and the expression levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor receptor b (PDGF-B) and the number of new blood vessels were measured by qRT-PCR and immunohistochemistry. VSMC and HUVEC cells were treated with hypoxia to induce in vivo I/R injury model. The protein expression of AKT, endothelial nitric oxide synthase (eNOS) and apoptosis-related protein levels were detected by western blotting. Besides, the positive staining rate and cell viability were tested by 5-bromo-2-deoxyuridine (Brdu)/4′,6-diamidino-2-phenylindole (DAPI) or DAPI/TdT-mediated dUTP Nick-End Labeling (TUNEL) staining and MTT assay.

Results

Cilostazol promoted angiogenesis by increasing the number of new blood vessels and up-regulating the expression of VEGF, HGF, bFGF and PDGF-B in myocardial I/R-injury rat model. The in vitro experiments showed that cilostazol increased the level of eNOS and AKT, and also enhanced cell proliferation in hypoxia-treated VSMC and HUVEC cells. Furthermore, after 8-Br-cAMP treatment, VEGF, HGF, bFGF, PDGF-B, p-AKT and p-eNOS expression were up-regulated, while cleaved-caspase 3 and cleaved-PARP expression were down-regulated. In addition, the effects of cilostazol on cell viability and apoptosis were aggravated by 8-Br-cAMP and attenuated after KT-5720 treatment.

Conclusion

Cilostazol could promote angiogenesis, increase cell viability and inhibit cell apoptosis, consequently protecting myocardial tissues against I/R-injury through activating cAMP.

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Correspondence to Jiangjin Li.

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Li, J., Xiang, X., Xu, H. et al. Cilostazol Promotes Angiogenesis and Increases Cell Proliferation After Myocardial Ischemia–Reperfusion Injury Through a cAMP-Dependent Mechanism. Cardiovasc Eng Tech 10, 638–647 (2019). https://doi.org/10.1007/s13239-019-00435-0

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