H<sub>2</sub>O<sub>2</sub> Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling
In diabetes, the enzyme arginase is upregulated, which may compete with endothelial nitric oxide (NO) synthase (eNOS) for their common substrate L-arginine and compromise NO-mediated vasodilation. However, this eNOS uncoupling can lead to superoxide production and possibly vasodilator hydrogen perox...
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/1/489 |
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| author | Naris Thengchaisri Lih Kuo Travis W. Hein |
| author_facet | Naris Thengchaisri Lih Kuo Travis W. Hein |
| author_sort | Naris Thengchaisri |
| collection | DOAJ |
| description | In diabetes, the enzyme arginase is upregulated, which may compete with endothelial nitric oxide (NO) synthase (eNOS) for their common substrate L-arginine and compromise NO-mediated vasodilation. However, this eNOS uncoupling can lead to superoxide production and possibly vasodilator hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) formation to compensate for NO deficiency. This hypothesis was tested in coronary arterioles isolated from pigs with 2-week diabetes after streptozocin injection. The NO-mediated vasodilation induced by flow and VEGF was abolished by NOS inhibitor L-NAME and phosphoinositide 3-kinase (PI3K) inhibitor wortmannin but was not affected by arginase inhibitor N<sup>ω</sup>-hydroxy-nor-L-arginine (nor-NOHA) or H<sub>2</sub>O<sub>2</sub> scavenger catalase in control pigs. With diabetes, this vasodilation was partially blunted, and the remaining vasodilation was abolished by catalase and wortmannin. Administration of L-arginine or nor-NOHA restored flow-induced vasodilation in an L-NAME sensitive manner. Diabetes did not alter vascular superoxide dismutase 1, catalase, and glutathione peroxidase mRNA levels. This study demonstrates that endothelium-dependent NO-mediated coronary arteriolar dilation is partially compromised in early type 1 diabetes by reducing eNOS substrate L-arginine via arginase activation. It appears that upregulated arginase contributes to endothelial NO deficiency in early diabetes, but production of H<sub>2</sub>O<sub>2</sub> during PI3K-linked eNOS uncoupling likely compensates for and masks this disturbance. |
| first_indexed | 2024-03-11T09:59:26Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:59:26Z |
| publishDate | 2022-12-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fbfb442539164a69a9bb6fba8ee025002023-11-16T15:34:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124148910.3390/ijms24010489H<sub>2</sub>O<sub>2</sub> Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS UncouplingNaris Thengchaisri0Lih Kuo1Travis W. Hein2Department of Medical Physiology, Cardiovascular Research Institute, School of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USADepartment of Medical Physiology, Cardiovascular Research Institute, School of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USADepartment of Medical Physiology, Cardiovascular Research Institute, School of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USAIn diabetes, the enzyme arginase is upregulated, which may compete with endothelial nitric oxide (NO) synthase (eNOS) for their common substrate L-arginine and compromise NO-mediated vasodilation. However, this eNOS uncoupling can lead to superoxide production and possibly vasodilator hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) formation to compensate for NO deficiency. This hypothesis was tested in coronary arterioles isolated from pigs with 2-week diabetes after streptozocin injection. The NO-mediated vasodilation induced by flow and VEGF was abolished by NOS inhibitor L-NAME and phosphoinositide 3-kinase (PI3K) inhibitor wortmannin but was not affected by arginase inhibitor N<sup>ω</sup>-hydroxy-nor-L-arginine (nor-NOHA) or H<sub>2</sub>O<sub>2</sub> scavenger catalase in control pigs. With diabetes, this vasodilation was partially blunted, and the remaining vasodilation was abolished by catalase and wortmannin. Administration of L-arginine or nor-NOHA restored flow-induced vasodilation in an L-NAME sensitive manner. Diabetes did not alter vascular superoxide dismutase 1, catalase, and glutathione peroxidase mRNA levels. This study demonstrates that endothelium-dependent NO-mediated coronary arteriolar dilation is partially compromised in early type 1 diabetes by reducing eNOS substrate L-arginine via arginase activation. It appears that upregulated arginase contributes to endothelial NO deficiency in early diabetes, but production of H<sub>2</sub>O<sub>2</sub> during PI3K-linked eNOS uncoupling likely compensates for and masks this disturbance.https://www.mdpi.com/1422-0067/24/1/489coronary microvascular diseaseendothelial dysfunctionnitric oxideoxidative stress |
| spellingShingle | Naris Thengchaisri Lih Kuo Travis W. Hein H<sub>2</sub>O<sub>2</sub> Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling International Journal of Molecular Sciences coronary microvascular disease endothelial dysfunction nitric oxide oxidative stress |
| title | H<sub>2</sub>O<sub>2</sub> Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling |
| title_full | H<sub>2</sub>O<sub>2</sub> Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling |
| title_fullStr | H<sub>2</sub>O<sub>2</sub> Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling |
| title_full_unstemmed | H<sub>2</sub>O<sub>2</sub> Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling |
| title_short | H<sub>2</sub>O<sub>2</sub> Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling |
| title_sort | h sub 2 sub o sub 2 sub mediates vegf and flow induced dilations of coronary arterioles in early type 1 diabetes role of vascular arginase and pi3k linked enos uncoupling |
| topic | coronary microvascular disease endothelial dysfunction nitric oxide oxidative stress |
| url | https://www.mdpi.com/1422-0067/24/1/489 |
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