Endothelin-1-Induced Microvascular ROS and Contractility in Angiotensin-II-Infused Mice Depend on COX and TP Receptors
Abstract
:1. Introduction
2. Materials and Methods
2.1. Mice
2.2. Animal Model and Angiotensin II Infusion
2.3. Measurement of Urinary 8-Isoprostane F2α and Thromboxane B2 (TxB2)
2.4. Protein Expression from Mesenteric Resistance Arterioles
2.5. Contractility and ROS Generation of Mesenteric Resistance Arterioles
2.6. Measurement of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Superoxide Dismutase (SOD) Activities in Mouse Aortas
2.7. Chemicals and Solutions
2.8. Statistical Analysis
3. Results
3.1. Mean Arterial Pressure (MAP) of Conscious Mice Infused with Angiotensin II
3.2. Basal Values and Urinary Biomarkers in TPR +/+ and −/− and COX1 +/+ and −/− Mice
3.3. Protein Expression in Mesenteric Resistance Arterioles
3.4. Contractile Responses of Mesenteric Resistance Arterioles to Phenylephrine (PE), U-46,619, and Endothelin 1 (ET-1)
3.5. Contractile Responses of Mesenteric Resistance Arterioles to Endothelin 1: Effect of Angiotensin II Infusion and of the Blockade of ROS, COX, and TxA2 Synthase in COX1 +/+ and −/− and TPR +/+ and −/− Mice
3.6. Generation of Reactive Oxygen Species (ROS) with Endothelin 1 in Mesenteric Resistance Arterioles
3.7. Activities of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Superoxide Dismutase (SOD) Isoforms in Aortas Stimulated by Endothelin 1 and Incubated with a Thromboxane Prostanoid Receptor Blocker or a Vehicle in Mice Infused with Angiotensin II at a Slow Pressor or Sub-Threshold Rate
4. Discussion
4.1. ROS are Downstream from the Activation of COX or TPRs in Mice Infused for Two Weeks with Ang II
4.2. Both COX1 and 2 Participate in ET-1-Induced ROS Generation in Mesenteric Resistance Arterioles from Ang-II-Infused Mice
4.3. Sources of ET-1 Stimulated ROS in Blood Vessels of Ang-II-Infused Mice
4.4. COX1 and 2 and TPRs are Absolute Requirements for Microvascular ROS Generation with ET-1 in Ang-II-Infused Mice
5. Conclusions
6. Clinical Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Variable | Vehicle | Ang II Infusion | By ANOVA, Effect of | ||||
---|---|---|---|---|---|---|---|
TPR +/+ | TPR −/− | TPR +/+ | TPR −/− | TPR Genotype | Ang II | Interaction | |
MAP (mmHg) | 92 ± 3 | 94 ± 2 | 108 ± 4 * | 97 ± 3 | NS | P < 0.05 | P < 0.05 |
Body weight (g) | 27.5 ± 0.5 | 27.0 ± 0.7 | 26.5 ± 0.7 | 27.4 ± 0.8 | NS | NS | NS |
Heart weight/Bwt (g) | 0.99 ± 0.05 | 1.09 ± 0.10 | 0.89 ± 0.08 | 0.95 ± 0.12 | NS | NS | NS |
Aorta (mg) | 0.15 ± 0.01 | 0.16 ± 0.007 | 0.16 ± 0.005 | 0.15 ± 0.006 | NS | NS | NS |
MRA lumen (µm) | 139 ± 12 | 135 ± 6 | 121 ± 8 | 134 ± 5 | NS | NS | NS |
MRA media (µm) | 42 ± 5 | 43 ± 7 | 51 ± 5 * | 48 ± 6 | NS | P < 0.05 | NS |
MRA M/L ratio | 0.30 ± 0.06 | 0.31 ± 0.09 | 0.42 ± 0.08 * | 0.35 ± 0.07 † | NS | P < 0.05 | P < 0.05 |
Urinary 8-Isoprostane F2α (ng/mg creatinine) | 1.43 ± 0.18 | 1.79 ± 0.11 | 2.23 ± 0.13 * | 1.66 ± 0.07 † | NS | P < 0.05 | P < 0.05 |
Urinary TxB2 (ng/mg creatinine) | 1.18 ± 0.07 | 0.92 ± 0.12 | 1.80 ± 0.13 * | 1.18 ± 0.0 † | P < 0.05 | P < 0.05 | NS |
Variable | Vehicle | Ang II Infusion | By ANOVA, Effect of | ||||
---|---|---|---|---|---|---|---|
COX1 +/+ | COX1 −/− | COX1 +/+ | COX1 −/− | COX1 Genotype | Ang II | Interaction | |
MAP (mmHg) | 88 ± 3 | 94 ± 3 | 124 ± 4 * | 112 ± 3† | P < 0.05 | P < 0.05 | P < 0.05 |
Body weight (BW, g) | 26.5 ± 0.6 | 28.0 ± 0.8 | 27.5 ± 0.6 | 29.4 ± 0.9 | NS | NS | NS |
Heart weight (g) | 0.94 ± 0.05 | 0.98 ± 0.11 | 1.05 ± 0.07 | 0.99 ± 0.12 | NS | NS | NS |
Aorta (g) | 0.15 ± 0.01 | 0.16 ± 0.007 | 0.16 ± 0.005 | 0.15 ± 0.006 | NS | NS | NS |
MRA lumen (µm) | 142 ± 9 | 135 ± 5 | 123 ± 7 | 132 ± 5 | NS | NS | NS |
MRA media (µm) | 43 ± 4 | 41 ± 5 | 55 ± 6 * | 47 ± 5 | NS | P < 0.05 | NS |
MRA M/L ratio | 0.30 ± 0.07 | 0.31 ± 0.04 | 0.44 ± 0.05 * | 0.36 ± 0.06 | NS | P < 0.05 | P < 0.05 |
Urinary 8-Isoprostane F2α (ng·mg creatinine-1) | 1.44 ± 0.10 | 1.45 ± 0.22 | 2.11 ± 0.19 * | 1.79 ± 0.21† | NS | P < 0.05 | P < 0.05 |
Urinary TxB2 (ng·mg creatinine-1) | 1.0 ± 0.05 | 0.99 ± 0.06 | 1.32 ± 0.07 * | 1.03 ± 0.06 † | NS | P < 0.05 | NS |
Added to the Bath | Vehicle Infusion | Ang II Infusion | By ANOVA, Effect of | ||||
TPR +/+ | TPR −/− | TPR +/+ | TPR −/− | TPR Genotype | Ang II Infusion | Interaction | |
PSS (%) | 94 ± 6 | 96 ± 3 | 122 ± 5 *,† | 93 ± 7 † | NS | P < 0.05 | P < 0.05 |
Tempol (%) | 90 ± 5 | 91 ± 4 | 86 ± 5 # | 92 ± 5 | NS | NS | NS |
SC-560 (%) | 89 ± 7 | 90 ± 5 | 74 ± 7 # | 86 ± 7 | NS | NS | NS |
Paracoxib (%) | 91 ± 4 | 92 ± 3 | 94 ± 10 # | 82 ± 6 | NS | NS | NS |
SC + Paracoxib (%) | 86 ± 7 | 88 ± 5 | 85 ± 7 # | 87 ± 2 | NS | NS | NS |
OKY-046NA (%) | 88 ± 6 | 92 ± 4 | 90 ± 2 # | 94 ± 3 | NS | NS | NS |
Added to the Bath | Vehicle Infusion | Ang II Infusion | By ANOVA, Effect of | ||||
COX1 +/+ | COX1 −/− | COX1 +/+ | COX1 −/− | COX1 Genotype | Ang II Infusion | Interaction | |
PSS (%) | 75 ± 3 | 76 ± 7 | 104 ± 3 *,† | 88 ± 4 † | NS | P < 0.05 | P < 0.05 |
Tempol (%) | 70 ± 4 | 71 ± 5 | 70 ± 3 # | 72 ± 6 | NS | NS | NS |
SC-560 (%) | 69 ± 5 | 59 ± 9 # | |||||
Paracoxib (%) | 72 ± 6 | 70 ± 4 | 76 ± 6 # | 67 ± 9 | NS | NS | NS |
SC + Paracoxib (%) | 68 ± 5 | 64 ± 4 # | |||||
OKY-046NA (%) | 72 ± 6 | 73 ± 6 | 86 ± 6 *,# | 76 ± 6 | NS | P < 0.05 | NS |
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Wilcox, C.S.; Wang, C.; Wang, D. Endothelin-1-Induced Microvascular ROS and Contractility in Angiotensin-II-Infused Mice Depend on COX and TP Receptors. Antioxidants 2019, 8, 193. https://doi.org/10.3390/antiox8060193
Wilcox CS, Wang C, Wang D. Endothelin-1-Induced Microvascular ROS and Contractility in Angiotensin-II-Infused Mice Depend on COX and TP Receptors. Antioxidants. 2019; 8(6):193. https://doi.org/10.3390/antiox8060193
Chicago/Turabian StyleWilcox, Christopher S., Cheng Wang, and Dan Wang. 2019. "Endothelin-1-Induced Microvascular ROS and Contractility in Angiotensin-II-Infused Mice Depend on COX and TP Receptors" Antioxidants 8, no. 6: 193. https://doi.org/10.3390/antiox8060193