Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes

• Published in: International journal of molecular sciences 2023-05, Vol.24 (9), p.8375
• Main Authors: Ruisanchez, Éva, Janovicz, Anna, Panta, Rita Cecília, Kiss, Levente, Párkányi, Adrienn, Straky, Zsuzsa, Korda, Dávid, Liliom, Károly, Tigyi, Gábor, Benyó, Zoltán
• Format: Article
• Language: English
• Subjects: Analysis; Animal models; Animals; Aorta; Blood vessels; Cardiovascular system; Ceramidase; Coronary vessels; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; Dilatation; Disease Models, Animal; endothelial nitric oxide synthase; Endothelium; Endothelium, Vascular - metabolism; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Kinases; Membrane lipids; Metabolism; Metabolites; Mice; NG-Nitroarginine methyl ester; NG-Nitroarginine Methyl Ester - metabolism; NG-Nitroarginine Methyl Ester - pharmacology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Sphingolipids; Sphingomyelin phosphodiesterase; Sphingomyelin Phosphodiesterase - metabolism; sphingomyelinase; Sphingosine; Thorax; thromboxane prostanoid receptor; Type 2 diabetes; Vasoactive agents; Vasoconstriction; Vasodilation; vasorelaxation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24098375

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 ( / , 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.