Angiotensin II-Derived Reactive Oxygen Species Promote Angiogenesis in Human Late Endothelial Progenitor Cells Through H
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Angiotensin II-Derived Reactive Oxygen Species Promote Angiogenesis in Human Late Endothelial Progenitor Cells Through Heme Oxygenase-1 via ERK1/2 and AKT/PI3K Pathways Jingting Mai,1,2 Qiong Qiu,1,2 Yong Qing Lin,1,2 Nian Sang Luo,1,2 Hai Feng Zhang,1,2 Zhu Zhi Wen,1,2 Jing Feng Wang,1,2,3 and Chen YangXin1,2,3
Abstract—Angiotensin II (Ang II), the main component of renin-angiotensin system, could mediate pathogenic angiogenesis in cardiovascular disorders. Late endothelial progenitor cells (EPCs) possess potent self-renewal and angiogenic potency superior to early EPCs, but few study focused on the crosstalk between Ang II and late EPCs. We observed that Ang II could increase reactive oxygen species (ROS) and promote capillary formation in late EPCs. Ang II-derived ROS could also upregulate heme oxygenase-1 (HO-1) expression, and treating late EPCs with HO-1 small interfering RNA or heme oxygenase inhibitor (HO inhibitor) could inhibit Ang II-induced tube formation and increase ROS level and apoptosis rate. In addition, PD98059 and LY294002 pretreatment attenuated Ang II-induced HO-1 expression. Accordingly, Ang II-derived ROS could promote angiogenesis in late EPCs by inducing HO-1 expression via ERK1/2 and AKT/PI3K pathways, and we believe HO-1 might be a promising intervention target in EPCs due to its potent proangiogenic, antioxidant, and antiapoptosis potentials. KEY WORDS: endothelial progenitor cells; heme oxygenase-1; angiotensin II; angiogenesis.
INTRODUCTION The renin-angiotensin system (RAS) was well accepted to be crucial in the pathogenesis of diverse clinical conditions including cardiovascular disorders and cancer [1–4]. Recently, the role of RAS in maintenance of vascular homeostasis has become of scientific interest [5]. Angiotensin II (Ang II), the main component of RAS, could promote angiogenesis in endothelial cells [6], and Ang II
Jingting Mai and Qiong Qiu contributed equally to this paper. Electronic supplementary material The online version of this article (doi:10.1007/s10753-013-9806-9) contains supplementary material, which is available to authorized users. 1
Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China 2 Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, 510120, China 3 To whom correspondence should be addressed at Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, 510120, China. E-mail: [email protected]; [email protected]
receptor type 1 (AT1) knockout mice had poor angiogenesis ability in ischemia and tumor models [3, 7]. Furthermore, Ang II could induce oxidative stress in various cell types [8–11], and moderate level of oxidative stress contributed to angiogenesis [10]. However, the mechanism of Ang II-mediated angiogenesis was still unclear. Endothelial progenitor cells (EPCs), the precursor cells of endothelial cells, play essential roles in physiologic and pathologic angiogenesis [12–15]. It has two different types including early and late EPCs. Exi
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