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Prolonged mechanical stretch is associated with upregulation of hypoxia-inducible factors and reduced contraction in rat inferior vena cava  Chung S.

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Presentation on theme: "Prolonged mechanical stretch is associated with upregulation of hypoxia-inducible factors and reduced contraction in rat inferior vena cava  Chung S."— Presentation transcript:

1 Prolonged mechanical stretch is associated with upregulation of hypoxia-inducible factors and reduced contraction in rat inferior vena cava  Chung S. Lim, MBBS, MRCS, Xiaoying Qiao, MD, PhD, Ossama M. Reslan, MD, Yin Xia, MD, PhD, Joseph D. Raffetto, MD, Ewa Paleolog, PhD, Alun H. Davies, DM, FRCS, Raouf A. Khalil, MD, PhD  Journal of Vascular Surgery  Volume 53, Issue 3, Pages (March 2011) DOI: /j.jvs Copyright © 2011 Society for Vascular Surgery Terms and Conditions

2 Fig 1 Effects of prolonged increases in basal tension and hypoxia-inducible factor (HIF) modulators are shown on phenylephrine (PHE)-induced contraction in rat inferior vena cava (IVC). IVC segments were subjected to initial 0.5-g basal tension for 1 hour and a control PHE (10–5M) contraction was elicited. The veins were then subjected to 0.5-g or 2-g tension for 18 hours, and a second PHE (10–5M) contraction was elicited. Some of the tissues subjected to 2-g tension were also treated with the HIF inhibitor U0126 (10–5M), 17-[2-(dimethylamino)ethyl] amino-17-desmethoxygeldanamycin (17-DMAG; 10–5M), or echinomycin (10–6M), or with the HIF stabilizer dimethyloxallyl glycine (DMOG; 10–4M). The second PHE contraction was measured as fold-change compared with the initial control contraction at 0.5-g basal tension for 1 hour. Data columns represent means ± SEM (error bars) of 7 to 10 experiments. *Significantly reduced (P < .05) compared with veins under 0.5-g tension for 18 hours (dotted column). §Significantly enhanced (P < .05) compared with veins under 2-g tension for 18 hours (black column). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

3 Fig 2 Effects of prolonged increases in basal tension and hypoxia-inducible factor (HIF) modulators are shown on KCl-induced contraction in rat inferior vena cava (IVC). IVC segments were subjected to initial 0.5-g basal tension for 1 hour, and a control contraction to membrane depolarization by 96mM KCl was elicited. The veins were then subjected to 0.5-g or 2-g tension for 18 hours, and a second KCl (96mM) contraction was elicited. Some of the veins subjected to 2-g tension were also treated with the HIF inhibitor U0126 (10–5M), 17-[2-(dimethylamino)ethyl] amino-17-desmethoxygeldanamycin (17-DMAG; 10–5M), or echinomycin (10–6M), or with the HIF stabilizer dimethyloxallyl glycine (DMOG; 10–4M). The second KCl contraction was measured as fold-change compared with the initial control contraction at 0.5-g basal tension for 1 hour. Data columns represent means ± SEM (error bars) of 7 to 10 experiments. *Significantly reduced (P < .05) compared with veins under 0.5-g tension for 18 hours (dotted column). §Significantly enhanced (P < .05) compared with veins under 2-g tension for 18 hours (black column). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

4 Fig 3 Effects of prolonged increases in basal tension and hypoxia-inducible factor (HIF) modulators are shown on the expression of (A) HIF-1α and (B) HIF-2α messenger RNA (mRNA) in rat inferior vena cava (IVC). IVC segments were subjected to 0.5-g basal tension for 1 hour, 0.5-g tension for 18 hours, high 2-g tension for 18 hours, and prolonged 2-g tension plus the HIF inhibitor U0126 (10–5M), 17-[2-(dimethylamino)ethyl] amino-17-desmethoxygeldanamycin (17-DMAG; 10–5M), or echinomycin (10–6M), or the HIF stabilizer dimethyloxallyl glycine (DMOG; 10–4M). The veins were rapidly frozen for mRNA analysis. Reverse transcription-polymerase chain reaction analysis was performed to measure the expression of (A) HIF-1α and (B) HIF-2α mRNA relative to the housekeeping gene α-actin. Data represent means ± SEM (error bars), n = 4. *Significantly increased (P < .05) compared with veins under 0.5-g tension for 18 hours (dotted column). §Significantly reduced (P < .05) compared with veins under 2-g tension for 18 hours (black column). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

5 Fig 4 Effects of prolonged increases in basal tension and hypoxia-inducible factor (HIF) modulators on the expression of (A) matrix metalloprotease (MMP)-2 and (B) MMP-9 in rat inferior vena cava (IVC). IVC segments were subjected to 0.5-g basal tension for 1 hour, 0.5-g tension for 18 hours, high 2-g tension for 18 hours, and prolonged 2-g tension plus the HIF inhibitor U0126 (10–5M), 17-[2-(dimethylamino)ethyl] amino-17-desmethoxygeldanamycin (17-DMAG; 10–5M), or echinomycin (10–6M), or the HIF stabilizer dimethyloxallyl glycine (DMOG; 10–4M). The veins were rapidly frozen for messenger RNA (mRNA) analysis. Reverse transcription-polymerase chain reaction analysis was performed to measure the expression of (A) MMP-2 and (B) MMP-9 mRNA relative to the housekeeping gene α-actin. Data represent means ± SEM (error bars), n = 4. *Significantly increased (P < .05) compared with veins under 0.5-g tension for 18 hours (dotted column). §Significantly reduced (P < .05) compared with veins under 2-g tension for 18 hours (black column). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

6 Fig 5 Effects of prolonged increases in basal tension are shown on the protein amount of hypoxia-inducible factor (HIF)-1α, HIF-2α, matrix metalloprotease (MMP)-2, and MMP-9 in rat inferior vena cava (IVC). IVC segments were subjected to 0.5-g basal tension for 1 hour or high 2-g tension for 18 hours. Western blot analysis was performed to measure the protein amount of (A) HIF-1α, (B) HIF-2α, (C) MMP-2, and (D) MMP-9 relative to the housekeeping protein α-actin. Data represent means ± SEM (error bars), n = 4 to 8 experiments. *Significantly increased (P < .05) compared with control veins under 0.5-g basal tension for 1 hour. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

7 Fig 6 This diagram depicts the potential relation between mechanical vein wall stretch, hypoxia-inducible factor (HIF) and matrix metalloprotease (MMP) expression, and vein relaxation. Also shown are different HIF modulators and their site of action. 17-DMAG, 17-[2-(dimethylamino)ethyl] amino-17-desmethoxygeldanamycin; DMOG, dimethyloxallyl glycine; HIF-OH, hydroxylated hypoxia-inducible factor; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

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