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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

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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 cross-talk 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.

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Acknowledgments

This study was supported by a grant from the National Natural Science Foundation of China (nos. 81100101 and 81270212), Yat-sen Scholarship for Young Scientist, and Young Teacher Support Project by Sun Yat-sen University for Chen Yangxin.

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Authors and Affiliations

  1. Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China

    **gting Mai, Qiong Qiu, Yong Qing Lin, Nian Sang Luo, Hai Feng Zhang, Zhu Zhi Wen, **g Feng Wang & Chen Yang**n

  2. Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, 510120, China

    **gting Mai, Qiong Qiu, Yong Qing Lin, Nian Sang Luo, Hai Feng Zhang, Zhu Zhi Wen, **g Feng Wang & Chen Yang**n

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Correspondence to **g Feng Wang or Chen Yang**n.

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**gting Mai and Qiong Qiu contributed equally to this paper.

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Fig. SI

VEGFR-2 and p-NOS levels were investigated in early and late EPCs after exposure to Ang II. The qRT-PCR was used to examine mRNA expression of VEGFR-2 (A) and protein level was examined by flow cytometry (B). Protein levels of p-eNOS (Ser1177) were tested by western blot. Protein levels of p-eNOS were normalized to the housekee** protein beta-tubulin (C). Three independent experiments were performed. qRT-PCR results are expressed as mean ± SEM and presented by percentage of the control group. *P < 0.05 compared to control group (JPEG 47 kb)

High-resolution image (TIFF 637 kb)

Fig. SII

PEG-SOD was an appropriate antioxidant for abolishing the ROS induced by Ang II in late EPCs. (A) Intracellular ROS was detected by means of an oxidation-sensitive fluorescent probe (DCFH-DA) used flow cytometry. Late EPCs were exposed to Ang II (100 nM) for 48 h with vehicle or PEG-SOD (50 U/ml), N-acetyl-l-cysteine (NAC; 10 mM) and apocynin (selective inhibitor of NADPH oxidase;100 μM) (n = 3). (B) Effects of NAC and PEG-SOD in the angiogenesis function were examined. Late EPCs were treated with vehicle or with NAC or PEG-SOD for 24 h (n = 3). Results are expressed as mean ± SEM and presented by percentage of the control group (JPEG 28 kb)

High-resolution image (TIFF 303 kb)

Fig. SIII

Ang II stimulated HO-1 expression in late EPCs. The qRT-PCR showed HO-1 mRNA levels for indicated concentrations (0.1, 1, 10, 100 nM) (A) and time (4, 12, 24 h) (B) under Ang II stimulation (n = 3). # P < 0.05 compared to control group; * P < 0.05 compared to Ang 100 nM 12 h group. Western blots showed HO-1 protein levels for indicated concentrations (1, 10 nM, 100 nM, 1,000 mM) (C) and time (12, 24, 36, and 48 h) (D) under Ang II stimulation (n = 3). Data were normalized to the housekee** protein beta-tubulin # P < 0.05 compared to control group; * P < 0.05 compared to Ang 100 nM 24-h group. Results are expressed as mean ± SEM and presented by percentage of the control group. # P < 0.05 compared to control group (JPEG 69 kb)

High-resolution image (TIFF 1,011 kb)

Fig. SIV

HO-1 siRNA transfection effectively suppress Ang II-induced HO-1 expression and HO-1 inducer CoPPIX could significantly upregulate HO-1 expression in late EPCs. (A) PE conjugated HO-1 siRNA were used to elevate the transfection efficiency by fluorescence microscopy. HO-1 mRNA (C) and protein (D) expression were evaluated. Late EPCs were exposed to Ang II (100 nM) in presence of HO-1 siRNA (100 nM) or mock siRNA (100 nM). Cells were also treated with CoPPIX (50 μmol/L) alone. Protein levels of HO-1 were normalized to the housekee** protein beta-tubulin. Three independent experiments were performed. Results are expressed as mean ± SEM and presented by percentage of the control group. # P < 0.05 compared to control group. * P < 0.05 compared to Ang II group (JPEG 60 kb)

High-resolution image (TIFF 2,002 kb)

Fig. SV

Representative immunoblot showed p-ERK/ERK, p-AKT(Ser473)/AKT, p-p38/p38, p-JNK/JNK amounts of EPCs in response to Ang II for indicated time (0, 24, 48, and 72 h). VEGF was added to maintain the vitality of EPCs in every group, n = 3). Data were normalized to the housekee** protein GAPDH. # P < 0.05 compared to control group (JPEG 37 kb)

High-resolution image (TIFF 977 kb)

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Mai, J., Qiu, Q., Lin, Y.Q. et al. 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. Inflammation 37, 858–870 (2014). https://doi.org/10.1007/s10753-013-9806-9

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