期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 24, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/ijms24098375
关键词
sphingolipids; sphingomyelinase; vasorelaxation; endothelial nitric oxide synthase; type 2 diabetes; thromboxane prostanoid receptor
Enhanced sphingomyelinase activity in a mouse model of type 2 diabetes mellitus leads to altered vascular effects, showing marked relaxation in diabetic mice. Sphingomyelinase has dual vasoactive effects, including TP-mediated vasoconstriction and NO-mediated vasorelaxation.
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.
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