Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm disease Wei Wang, MD, PhD, Baohui Xu, MD, PhD, Haojun Xuan, MD, Yingbin Ge, MD,

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Presentation transcript:

Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm disease Wei Wang, MD, PhD, Baohui Xu, MD, PhD, Haojun Xuan, MD, Yingbin Ge, MD, PhD, Yan Wang, PhD, Lixin Wang, MD, PhD, Jianhua Huang, MD, Weiguo Fu, MD, PhD, Sara A. Michie, MD, Ronald L. Dalman, MD Journal of Vascular Surgery Volume 68, Issue 5, Pages 1538-1550.e2 (November 2018) DOI: 10.1016/j.jvs.2017.09.030 Copyright © 2017 Society for Vascular Surgery Terms and Conditions

Fig 1 Hypoxia-inducible factor 1α (HIF-1α) and its target gene messenger RNA (mRNA) levels are elevated in human and experimental aneurysmal aortae. A, Aneurysmal aortic segments were collected from 24 patients receiving open abdominal aortic aneurysm (AAA) repair and six organ donors for organ transplantation (control). Total RNA was extracted for evaluating expression of HIF-1α and its four target genes by quantitative real-time reverse transcription-polymerase chain reaction (PCR). B, Ten- to 12-week-old male mice received transient intra-aortic infusion of porcine pancreatic elastase (PPE) for aneurysm creation or phosphate-buffered saline (PBS) as nonaneurysmal control (n = 5-8 mice per group). Aortae were collected 2 weeks after the infusion; identical gene expression analyses were performed as in (A). The mRNA levels in aneurysmal aortae are presented as the fold changes relative to organ donor human (A) or PBS-infused nonaneurysmal mouse (B) aortae. Data are presented as mean ± standard deviation. One-sample t-test, #P < .1, *P < .05, and **P < .01 compared with organ donor aortae (A) or PBS-infused mouse aortae (B), where the value was set at 1 (dotted line). Glut-1, Glucose transporter 1; MMP2, matrix metalloproteinase 2; NOX2, NADPH oxidase 2; VEGF-A, vascular endothelial growth factor A. Journal of Vascular Surgery 2018 68, 1538-1550.e2DOI: (10.1016/j.jvs.2017.09.030) Copyright © 2017 Society for Vascular Surgery Terms and Conditions

Fig 2 Immunostaining of hypoxia-inducible factor 1α (HIF-1α) in aneurysmal and nonaneurysmal aortae. Formalin-fixed, paraffin-embedded sections were prepared from the aortae of mice 14 days after porcine pancreatic elastase (PPE; aneurysmal) or phosphate-buffered saline (PBS; nonaneurysmal) infusion as well as from abdominal aortic aneurysm (AAA) patients and nonaneurysmal normal organ donors. After antigen retrieval, aortic sections were stained with anti-HIF-1α monoclonal antibody (mAb) using a standard biotin-streptavidin-peroxidase technique. A and D, Many nuclear HIF-1α-expressing cells (brown) were observed in aortic adventitia of AAA mice (A) and patients (D). B and E, Very few cells in the aortic sections from the nonaneurysmal aortae of mice (B) or organ donors (E) stained positive with anti-HIF-1α mAb. C and F, No cells stained positive for negative control antibody in the aortic sections from aneurysmal mice (C) or patients (F). In addition, no staining was noted in the aortic section from nonaneurysmal mice or organ donor patients (not shown). These staining patterns were representative of at least three individuals in each group. Journal of Vascular Surgery 2018 68, 1538-1550.e2DOI: (10.1016/j.jvs.2017.09.030) Copyright © 2017 Society for Vascular Surgery Terms and Conditions

Fig 3 Systemic hypoxia-inducible factor 1α (HIF-1α) inhibitor treatment reduces the messenger RNA (mRNA) levels of HIF-1 target genes. Mice were given an HIF-1α inhibitor (50 mg/kg/d by gavage for 2-methoxyestradiol [2ME] or 2 mg/kg/d by gavage for digoxin) or an equal volume of vehicle beginning 1 day before porcine pancreatic elastase (PPE) infusion for a total of 14 days. Total RNA was extracted from the heart 2 weeks after PPE infusion for evaluating HIF-1α and its target gene expression. Message RNA levels in HIF-1α inhibitor-treated mice were presented as the percentage of the value in the vehicle treatment group (as 100%). n = 5-8 in each group. One-sample t-test, **P < .05 compared with vehicle treatment, where the value is set at 100% (dotted line). Glut-1, Glucose transporter 1; MMP2, matrix metalloproteinase 2; VEGF-A, vascular endothelial growth factor A. Journal of Vascular Surgery 2018 68, 1538-1550.e2DOI: (10.1016/j.jvs.2017.09.030) Copyright © 2017 Society for Vascular Surgery Terms and Conditions

Fig 4 Hypoxia-inducible factor 1α (HIF-1α) inhibitor treatment suppresses abdominal aortic aneurysm (AAA) formation. Male C57BL/6J mice at 10 to 12 weeks of age were given 2-methoxyestradiol (2ME; 50 mg/kg/d) or digoxin (2 mg/kg/d) by oral gavage beginning 1 day before and continuing for 13 days after porcine pancreatic elastase (PPE) infusion. There were five to eight mice in each group. A, Representative aortic ultrasound images at indicated days in PPE-infused mice treated with 2ME, digoxin, or vehicle. B, Mean and standard deviation of aortic diameters at the baseline level (day 0) and indicated days after PPE infusion. Two-way analysis of variance followed by Newman-Keuls post-test, *P < .05 and **P < .01 compared with vehicle treatment. C, Aneurysm incidence. An AAA was defined as a 50% or greater increase in aortic diameter above the baseline level. Kaplan-Meier analysis, *P < .05 and **P < .01 compared with vehicle treatment. D and E, Elastica-van Gieson (EVG) and smooth muscle cell (SMC) α-actin staining were performed and scored (1 [mild] to 4 [severe]) to evaluate medial elastin degradation and SMC depletion. Representative aortic elastin and SMC staining images (D). Quantification (mean and standard deviation) of elastin destruction and SMC depletion in individual groups (E). Nonparametric Mann-Whitney test, *P < .05 and **P < .01 compared with vehicle treatment group. Journal of Vascular Surgery 2018 68, 1538-1550.e2DOI: (10.1016/j.jvs.2017.09.030) Copyright © 2017 Society for Vascular Surgery Terms and Conditions

Fig 5 Hypoxia-inducible factor 1α (HIF-1α) inhibitor treatment attenuates mural inflammatory cell accumulation and angiogenesis. Aortic sections prepared from differentially treated mice were stained with monoclonal antibodies (mAbs) against CD68 (macrophages), CD3 (T cells), B220 (B cells), and CD31 (neovessels), respectively. A, Representative aortic immunostaining images for CD68+ macrophages, CD3+ T cells, B220+ B cells, and CD31+ neovessels. B-E, Quantification of aortic macrophages (B), T cells (C), B cells (D), and neoangiogenesis (E) in individual treatment groups. Data are expressed as mean and standard deviation; n = 5-8 mice in each group. Nonparametric Mann-Whitney test, **P < .01 compared with vehicle treatment. ACS, Aortic cross section; 2ME, 2-methoxyestradiol. Journal of Vascular Surgery 2018 68, 1538-1550.e2DOI: (10.1016/j.jvs.2017.09.030) Copyright © 2017 Society for Vascular Surgery Terms and Conditions

Fig 6 Hypoxia-inducible factor 1α (HIF-1α) inhibitor treatment does not affect the frequency of cytokine-producing CD4+ T cells. At sacrifice, single lymphocyte suspensions were prepared from the spleens of differentially treated mice. Staining for surface CD4 and intracellular cytokines was conducted following the BioLegend intracellular cytokine stain protocol and analyzed by fluorescence-activated cell sorting. Data are expressed as mean and standard deviation (in parentheses) of percentage of cytokine-producing cells in CD4+ T cells; n = 4 mice in each group. IFN-γ, Interferon γ; IL-17, interleukin 17; 2ME, 2-methoxyestradiol. Journal of Vascular Surgery 2018 68, 1538-1550.e2DOI: (10.1016/j.jvs.2017.09.030) Copyright © 2017 Society for Vascular Surgery Terms and Conditions

Fig 7 Hypoxia-inducible factor 1α (HIF-1α) inhibitor treatment limits progression of existing aneurysms. Mice were treated with 2-methoxyestradiol (2ME; 50 mg/kg/d; n = 7), digoxin (2 mg/kg/day; n = 10), or vehicle (n = 6) from day 4 after porcine pancreatic elastase (PPE) infusion until sacrifice for a total of 10 days. A, Representative aortic ultrasound images before (day 0) and 3 and 10 days after initiation of treatment. B, Mean and standard deviation of aortic enlargement compared with diameter immediately before initiation of treatment. Nonparametric Mann-Whitney test, **P < .01. C-G, Quantification of medial elastin degradation (elastica-van Gieson [EVG] stain, C) and smooth muscle cell (SMC) depletion (SMC α-actin, C), mural leukocytes (CD68 for macrophages, D), CD3 for T cells (E), and B220 for B cells (F) and mural neoangiogenesis (CD31, G). Data are expressed as mean and standard deviation. Nonparametric Mann-Whitney test, *P < .05 and **P < .01 compared with vehicle treatment group. ACS, Aortic cross section. Journal of Vascular Surgery 2018 68, 1538-1550.e2DOI: (10.1016/j.jvs.2017.09.030) Copyright © 2017 Society for Vascular Surgery Terms and Conditions

Fig 8 Limited influence of prolyl hydroxylase domain-containing protein (PHD) inhibitor treatment on experimental abdominal aortic aneurysms (AAAs). A, Aortae were collected from mice 14 days after phosphate-buffered saline (PBS; nonaneurysmal) and porcine pancreatic elastase (PPE; aneurysmal) infusion, and messenger RNA (mRNA) levels for PHD1, PHD2, and PHD3 were analyzed by real-time quantitative reverse transcription-polymerase chain reaction (PCR) assay. The mRNA levels in aneurysmal aortae were presented as fold changes relative to PBS-infused mouse aortae, where the value was set at 1 (dotted line). Data are expressed as mean and standard deviation from four mice in each group. One-sample t-test, **P < .01 compared with 1 (PBS-infused mouse aortae). B, Mice were treated daily with cobalt chloride (30 mg/kg intraperitoneally), JNJ-42041935 (100 μmol/kg by oral gavage), or vehicle beginning 1 day after PPE infusion. Data are expressed as mean ± standard deviation of aortic diameter from five mice in each group. Two-way analysis of variance followed by Newman-Keuls post-test, **P < .01 compared with vehicle treatment. Journal of Vascular Surgery 2018 68, 1538-1550.e2DOI: (10.1016/j.jvs.2017.09.030) Copyright © 2017 Society for Vascular Surgery Terms and Conditions