Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes
Sphingolipids are important biological mediators both in health and disease. We investigated the vascular effects of enhanced sphingomyelinase (SMase) activity in a mouse model of type 2 diabetes mellitus (T2DM) to gain an understanding of the signaling pathways involved. Myography was used to measu...
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/8375 |
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| author | Éva Ruisanchez Anna Janovicz Rita Cecília Panta Levente Kiss Adrienn Párkányi Zsuzsa Straky Dávid Korda Károly Liliom Gábor Tigyi Zoltán Benyó |
| author_facet | Éva Ruisanchez Anna Janovicz Rita Cecília Panta Levente Kiss Adrienn Párkányi Zsuzsa Straky Dávid Korda Károly Liliom Gábor Tigyi Zoltán Benyó |
| author_sort | Éva Ruisanchez |
| collection | DOAJ |
| description | Sphingolipids are important biological mediators both in health and disease. We investigated the vascular effects of enhanced sphingomyelinase (SMase) activity in a mouse model of type 2 diabetes mellitus (T2DM) to gain an understanding of the signaling pathways involved. Myography was used to measure changes in the tone of the thoracic aorta after administration of 0.2 U/mL neutral SMase in the presence or absence of the thromboxane prostanoid (TP) receptor antagonist SQ 29,548 and the nitric oxide synthase (NOS) inhibitor L-NAME. In precontracted aortic segments of non-diabetic mice, SMase induced transient contraction and subsequent weak relaxation, whereas vessels of diabetic (<i>Lepr<sup>db</sup></i>/<i>Lepr<sup>db</sup></i>, referred to as db/db) mice showed marked relaxation. In the presence of the TP receptor antagonist, SMase induced enhanced relaxation in both groups, which was 3-fold stronger in the vessels of db/db mice as compared to controls and could not be abolished by ceramidase or sphingosine-kinase inhibitors. Co-administration of the NOS inhibitor L-NAME abolished vasorelaxation in both groups. Our results indicate dual vasoactive effects of SMase: TP-mediated vasoconstriction and NO-mediated vasorelaxation. Surprisingly, in spite of the general endothelial dysfunction in T2DM, the endothelial NOS-mediated vasorelaxant effect of SMase was markedly enhanced. |
| first_indexed | 2024-03-11T04:16:34Z |
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| language | English |
| last_indexed | 2024-03-11T04:16:34Z |
| publishDate | 2023-05-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d26ee3d03f29434eb441fd5d1e64c6492023-11-17T23:08:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-01249837510.3390/ijms24098375Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 DiabetesÉva Ruisanchez0Anna Janovicz1Rita Cecília Panta2Levente Kiss3Adrienn Párkányi4Zsuzsa Straky5Dávid Korda6Károly Liliom7Gábor Tigyi8Zoltán Benyó9Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, H-1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, H-1094 Budapest, HungaryDepartment of Physiology, Semmelweis University, H-1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, H-1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, H-1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, H-1094 Budapest, HungaryInstitute of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, H-1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, H-1094 Budapest, HungarySphingolipids are important biological mediators both in health and disease. We investigated the vascular effects of enhanced sphingomyelinase (SMase) activity in a mouse model of type 2 diabetes mellitus (T2DM) to gain an understanding of the signaling pathways involved. Myography was used to measure changes in the tone of the thoracic aorta after administration of 0.2 U/mL neutral SMase in the presence or absence of the thromboxane prostanoid (TP) receptor antagonist SQ 29,548 and the nitric oxide synthase (NOS) inhibitor L-NAME. In precontracted aortic segments of non-diabetic mice, SMase induced transient contraction and subsequent weak relaxation, whereas vessels of diabetic (<i>Lepr<sup>db</sup></i>/<i>Lepr<sup>db</sup></i>, referred to as db/db) mice showed marked relaxation. In the presence of the TP receptor antagonist, SMase induced enhanced relaxation in both groups, which was 3-fold stronger in the vessels of db/db mice as compared to controls and could not be abolished by ceramidase or sphingosine-kinase inhibitors. Co-administration of the NOS inhibitor L-NAME abolished vasorelaxation in both groups. Our results indicate dual vasoactive effects of SMase: TP-mediated vasoconstriction and NO-mediated vasorelaxation. Surprisingly, in spite of the general endothelial dysfunction in T2DM, the endothelial NOS-mediated vasorelaxant effect of SMase was markedly enhanced.https://www.mdpi.com/1422-0067/24/9/8375sphingolipidssphingomyelinasevasorelaxationendothelial nitric oxide synthasetype 2 diabetesthromboxane prostanoid receptor |
| spellingShingle | Éva Ruisanchez Anna Janovicz Rita Cecília Panta Levente Kiss Adrienn Párkányi Zsuzsa Straky Dávid Korda Károly Liliom Gábor Tigyi Zoltán Benyó Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes International Journal of Molecular Sciences sphingolipids sphingomyelinase vasorelaxation endothelial nitric oxide synthase type 2 diabetes thromboxane prostanoid receptor |
| title | Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes |
| title_full | Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes |
| title_fullStr | Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes |
| title_full_unstemmed | Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes |
| title_short | Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes |
| title_sort | enhancement of sphingomyelinase induced endothelial nitric oxide synthase mediated vasorelaxation in a murine model of type 2 diabetes |
| topic | sphingolipids sphingomyelinase vasorelaxation endothelial nitric oxide synthase type 2 diabetes thromboxane prostanoid receptor |
| url | https://www.mdpi.com/1422-0067/24/9/8375 |
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