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ClC-3 deficiency prevents apoptosis induced by angiotensin II in endothelial progenitor cells via inhibition of NADPH oxidase

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Abstract

Endothelial progenitor cells (EPCs) play an important role in postnatal neovascularization and re-endothelialization in response to tissue ischemia and endothelial injury. It is reported that the circulating EPCs number is decreased during hypertension. However, the detailed mechanism is still unclear. Our previous studies have shown that ClC-3 chloride channel is up-regulated with the development of hypertension. This study aims to test whether ClC-3 participates in EPC apoptosis under the condition of increased oxidative stress in angiotensin II (Ang II)-induced hypertension. The results showed that stimulation with 10−6mol/L Ang II significantly up-regulated the endogenous ClC-3 expression and increased intracellular reactive oxygen species (ROS) generation in EPCs of wild type mice, accompanied by an enhanced NADPH oxidase activity and the expression of gp91phox (NOX-2), a key catalytic subunit of NADPH oxidase. However, these effects of Ang II were significantly reduced in EPCs of ClC-3−/− mice. Compared with control, treatment with Ang II induced EPCs apoptosis in wild type mice, concomitantly with declined Bcl-2/Bax ratio, depressed mitochondrial membrane potential and activation of poly(ADP-ribose) polymerase, which was remarkably prevented by both ClC-3 knockout and NADPH oxidase inhibitor apocynin. In addition, the role of ClC-3 deficiency in protecting EPCs against Ang II-induced oxidative stress and apoptosis was further confirmed in Ang II-infused hypertensive mice in vivo. In conclusion, ClC-3 deficiency inhibited Ang II-induced EPC apoptosis via suppressing ROS generation derived from NADPH oxidase.

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Acknowledgments

This work was supported by the Natural Science Foundation of China (Grant No. 30900578); and Science and Technology Planning Project of Guangzhou City, China (Grant No. 2011J2200077).

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Authors and Affiliations

  1. Department of Pharmacology, Cardiac and Cerebrovascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan 2 Rd, 510080, Guangzhou, People’s Republic of China

    Jing Liu, Fei-Fei Zhang, Lei Li, Jing Yang, Jie Liu, Yong-Yuan Guan & Yan-Hua Du

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  1. Jing Liu
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  2. Fei-Fei Zhang
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  3. Lei Li
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  4. Jing Yang
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  7. Yan-Hua Du
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Correspondence to Yan-Hua Du.

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Jing Liu and Fei-Fei Zhang contributed equally to this study.

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Liu, J., Zhang, FF., Li, L. et al. ClC-3 deficiency prevents apoptosis induced by angiotensin II in endothelial progenitor cells via inhibition of NADPH oxidase. Apoptosis 18, 1262–1273 (2013). https://doi.org/10.1007/s10495-013-0881-z

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