Abstract 13716: Coronary Artery Spasm Related to Thiol Oxidation and Rho a Activation in Aging Model with Senescence Marker Protein-30 (smp 30) Deficiency
We investigated the mechanism of coronary artery spasm related to oxidant stress with aging in senescence marker protein-30 (SMP30) deficient mice, because SMP30 decreases with aging and SMP30 knock-out (KO) mice show a short life with increased oxidant stress. To examine the effect of SMP30 on coronary artery vasomotor tone, we measured endothelium-dependent (acetylcholine, ACh, 5-hydroxytryptamine, 5-HT) and endothelium-independent (sodium nitroprusside, SNP) vasodilation of isolated, pressurized coronary arteries (84±8 µm, diameter) from SMP30 KO and wild-type (WT) mice (n=10, each). In SMP30 KO mice, ACh- or 5-HT-induced vasoconstriction was appeared, which changed vasodilation with dithiothreitol (DTT), a thiol-reducing agent. Treatment with Y-27632 (10 µM), Rho-kinase inhibitor, inhibited ACh- or 5-HT-induced vasoconstriction. In WT mice, ACh- or 5-HT-induced vasodilation was appeared, which was blunted with L-NAME. SNP-induced vasodilatation was comparable between SMP30 KO and WT mice. Administration of ACh (2 µg) or 5-HT (0.02 µg) from the aortic sinus induced transient ST-T segment elevation by electrocardiogram in SMP30 KO mice, which was prevented by intravenous administration of Y-27632 (0.02 µg), while ST-T segment change was not appeared in WT mice after ACh. To evaluate the thiol oxidation, we measured the fluorescence of monochlorobimane (MCB) or monobromotrimetylammoniobimane (MBB) in coronary arteries, which covalently label the reduced total thiols or extracellular-reduced thiols, respectively. The fluorescence level to MCB or MBB decreased in SMP30 KO mice, but restored to a level comparable to that of WT mice with treatment of Y-27632. From these results, SMP30 has a protective role to coronary artery spasm, which is induced by Rho-kinase activation with S-glutathionylation of cysteine residue in aging with chronic oxidant stress.
- © 2012 by American Heart Association, Inc.