PMID- 37176081 OWN - NLM STAT- MEDLINE DCOM- 20230515 LR - 20230515 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 9 DP - 2023 May 6 TI - Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes. LID - 10.3390/ijms24098375 [doi] LID - 8375 AB - 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 (Lepr(db)/Lepr(db), 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. FAU - Ruisanchez, Eva AU - Ruisanchez E AUID- ORCID: 0000-0001-7779-226X AD - Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, Hungary. AD - Eotvos Lorand Research Network and Semmelweis University (ELKH-SE) Cerebrovascular and Neurocognitive Disorders Research Group, H-1052 Budapest, Hungary. FAU - Janovicz, Anna AU - Janovicz A AD - Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, Hungary. AD - Eotvos Lorand Research Network and Semmelweis University (ELKH-SE) Cerebrovascular and Neurocognitive Disorders Research Group, H-1052 Budapest, Hungary. FAU - Panta, Rita Cecilia AU - Panta RC AD - Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, Hungary. FAU - Kiss, Levente AU - Kiss L AUID- ORCID: 0000-0003-1514-9978 AD - Department of Physiology, Semmelweis University, H-1094 Budapest, Hungary. FAU - Parkanyi, Adrienn AU - Parkanyi A AD - Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, Hungary. FAU - Straky, Zsuzsa AU - Straky Z AD - Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, Hungary. FAU - Korda, David AU - Korda D AD - Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, Hungary. FAU - Liliom, Karoly AU - Liliom K AUID- ORCID: 0000-0002-7177-6872 AD - Institute of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, Hungary. FAU - Tigyi, Gabor AU - Tigyi G AUID- ORCID: 0000-0001-5371-171X AD - Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, Hungary. AD - Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. FAU - Benyo, Zoltan AU - Benyo Z AUID- ORCID: 0000-0001-6015-0359 AD - Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, Hungary. AD - Eotvos Lorand Research Network and Semmelweis University (ELKH-SE) Cerebrovascular and Neurocognitive Disorders Research Group, H-1052 Budapest, Hungary. LA - eng GR - K-112964/Hungarian National Research, Development, and Innovation Office/ GR - K-125174/Hungarian National Research, Development, and Innovation Office/ GR - K-139230/Hungarian National Research, Development, and Innovation Office/ GR - PD-132851/Hungarian National Research, Development, and Innovation Office/ GR - 2020-1.1.6-JOVO-2021-00010/Ministry of Innovation and Technology of Hungary from the NRDI Fund/ GR - 2020-1.1.6-JOVO-2021-00013/Ministry of Innovation and Technology of Hungary from the NRDI Fund/ GR - TKP2021-EGA-25/Ministry of Innovation and Technology of Hungary from the NRDI Fund/ PT - Journal Article DEP - 20230506 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase) RN - V55S2QJN2X (NG-Nitroarginine Methyl Ester) RN - 31C4KY9ESH (Nitric Oxide) RN - 0 (Enzyme Inhibitors) SB - IM MH - Mice MH - Animals MH - *Nitric Oxide Synthase Type III/metabolism MH - Vasodilation MH - Sphingomyelin Phosphodiesterase/metabolism MH - NG-Nitroarginine Methyl Ester/pharmacology/metabolism MH - *Diabetes Mellitus, Type 2/metabolism MH - Nitric Oxide/metabolism MH - Disease Models, Animal MH - Endothelium, Vascular/metabolism MH - Enzyme Inhibitors/pharmacology/metabolism PMC - PMC10179569 OTO - NOTNLM OT - endothelial nitric oxide synthase OT - sphingolipids OT - sphingomyelinase OT - thromboxane prostanoid receptor OT - type 2 diabetes OT - vasorelaxation COIS- The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analysis, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. EDAT- 2023/05/13 15:12 MHDA- 2023/05/15 11:42 PMCR- 2023/05/06 CRDT- 2023/05/13 01:30 PHST- 2023/02/28 00:00 [received] PHST- 2023/04/30 00:00 [revised] PHST- 2023/05/04 00:00 [accepted] PHST- 2023/05/15 11:42 [medline] PHST- 2023/05/13 15:12 [pubmed] PHST- 2023/05/13 01:30 [entrez] PHST- 2023/05/06 00:00 [pmc-release] AID - ijms24098375 [pii] AID - ijms-24-08375 [pii] AID - 10.3390/ijms24098375 [doi] PST - epublish SO - Int J Mol Sci. 2023 May 6;24(9):8375. doi: 10.3390/ijms24098375.