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Transforming growth factor-β type I receptor/ALK5 contributes to doxazosin-induced apoptosis in H9C2 cells

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Abstract

The mechanism of doxazosin-induced apoptosis through α1-adrenoceptor-independent pathway has been reported in various types of cell models. However, the molecular events involved in this effect are still not fully discovered. In present study, we proposed that the transforming growth factor-β type I receptor (TβRI/ALK5) may contribute to the doxazosin-induced apoptosis in H9C2 cardiomyoblasts. Via the detection of cell viability, apoptotic nuclei, and caspase-3 activity, we found that doxazosin induced concentration- and time-dependent apoptosis in H9C2 cells. The cell apoptosis induced by 30 μM doxazosin was exacerbated by the addition of 10 ng/ml transforming growth factor-β1 (TGF-β1). Doxazosin or TGF-β1 alone respectively elevated p38 mitogen-activated protein kinases (MAPK) and Smad3 protein phosphorylation in H9C2 cells. However, the cotreatment of doxazosin and TGF-β1 attenuated the TGF-β1-induced Smad3 protein phosphorylation and increased doxazosin-induced p38 MAPK protein phosphorylation. Furthermore, inhibitors of TβRI/ALK5 (SB431542) and p38 MAPK (SB202190) or TβRI/ALK5 knockdown all dramatically reduced the doxazosin-induced apoptosis in H9C2 cells. In conclusion, our results demonstrated that TβRI/ALK5-p38 MAPK phosphorylation signaling pathway could contribute to doxazosin-induced cell apoptosis, which could be further enhanced by TGF-β1 in association with attenuating Smad3 phosphorylation in H9C2 cells.

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Acknowledgments

The authors thank Wen-Chun Wei for excellent technical assistance. This work was supported by National Science Council, Taiwan (NSC 97-2323-B-002-007).

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Authors and Affiliations

  1. Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Rd, Taipei, 100, Taiwan

    Yi-Fan Yang, Wen-Pin Chen & Ming-Jai Su

  2. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Yi-Fan Yang & Chau-Chung Wu

  3. Department of Primary Care Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    Chau-Chung Wu

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  1. Yi-Fan Yang
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  2. Chau-Chung Wu
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Correspondence to Ming-Jai Su.

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Yang, YF., Wu, CC., Chen, WP. et al. Transforming growth factor-β type I receptor/ALK5 contributes to doxazosin-induced apoptosis in H9C2 cells. Naunyn-Schmied Arch Pharmacol 380, 561–567 (2009). https://doi.org/10.1007/s00210-009-0449-1

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  • DOI: https://doi.org/10.1007/s00210-009-0449-1

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