Abstract:
OBJECTIVE:We recently demonstrated in our swine model of coronary artery spasm that enhanced myosin light chain (MLC) phosphorylations (both MLC mono- and diphosphorylations) play a central role in the pathogenesis of the spasm. However, the molecular mechanism for and the phosphorylation sites for the enhanced MLC phosphorylations were unknown. In the present study, we addressed these points using hydroxyfasudil, a novel inhibitor of protein kinases, which we found preferentially inhibits Rho-kinase. METHODS:The specificity of the inhibitory effects of hydroxyfasudil on Rho-kinase, MLCK, MRCK beta and PKC were examined by kinase assay in vitro. The left porcine coronary artery was chronically treated with interleukin-1 beta (IL-1 beta, 2.5 micrograms). Two weeks after the operation, coronary artery vasomotion was examined both in vivo and in vitro. MLC phosphorylations were examined by Western blot analysis and the sites for the phosphorylations by anti-phosphorylated MLC antibodies that identified the monophosphorylation site as Ser19 and diphophorylation sites as Ser19/Thr18 of MLC. RESULTS:Inhibitory effects of hydroxyfasudil was at least 100 times more potent for Rho-kinase as compared with other protein kinases tested. Intracoronary serotonin (10 micrograms/kg) caused coronary hyperconstriction at the IL-1 beta-treated site in vivo, which was dose-dependently inhibited by hydroxyfasudil (p < 0.01). The coronary segment taken from the spastic site also showed hypercontractions to serotonin in vitro, which were again dose-dependently inhibited by hydroxyfasudil (p < 0.01). Western blot analysis showed that MLC monophosphorylation was significantly greater in the spastic segment than in the control segment, while MLC diphosphorylation was noted only at the spastic segment (p < 0.01). The sites for the mono- and diphosphorylated MLC were identified as the monophosphorylated site Ser19 and diphosphorylated sites Ser19/Thr18 of MLC, respectively. Both types of MLC phosphorylations at the spastic segment were markedly inhibited by hydroxyfasudil (p < 0.01). CONCLUSION:These results indicate that hydroxyfasudil-sensitive Rho-kinase-mediated pathway appears to mediate the enhanced MLC phosphorylations (on Ser19 and Ser19/Thr18 residues) and plays a central role in the pathogenesis of coronary artery spasm.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Shimokawa H,Seto M,Katsumata N,Amano M,Kozai T,Yamawaki T,Kuwata K,Kandabashi T,Egashira K,Ikegaki I,Asano T,Kaibuchi K,Takeshita Adoi
10.1016/s0008-6363(99)00144-3subject
Has Abstractpub_date
1999-09-01 00:00:00pages
1029-39issue
4eissn
0008-6363issn
1755-3245pii
S0008-6363(99)00144-3journal_volume
43pub_type
杂志文章abstract:OBJECTIVE:We recently showed that mitochondrial coupling factor 6 (CF6) is present as a pressor substance and a prostacyclin inhibitor in systemic circulation. However, the regulation mechanism for circulating CF6 is unknown. We investigated the role of tumor necrosis factor-alpha (TNF-alpha) in the generation and rele...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2004.01.031
更新日期:2004-06-01 00:00:00
abstract:AIMS:Cardiac hypertrophy is characterized by a shift in metabolic substrate utilization, but the molecular events underlying the metabolic remodelling remain poorly understood. We explored metabolic remodelling and mitochondrial dysfunction in cardiac hypertrophy and investigated the cardioprotective effects of choline...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvy217
更新日期:2019-03-01 00:00:00
abstract:AIMS:Human C-peptide has a beneficial effect on the prevention of diabetic neuropathy, nephropathy, and vascular complications; however, its role in protection against increased vascular permeability in diabetes remains unclear. Our purpose was to explore the potential protective role of C-peptide against microvascular...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvt238
更新日期:2014-01-01 00:00:00
abstract::Ultrasound has become a useful high resolution imaging modality for examining the cardiac microcirculation. With the use of microbubbles as an ultrasound contrast agent, ultrasound can be utilized to image the microcirculation and detect capillary flow abnormalities in acute ischaemia. A wide range of ultrasound frequ...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvp206
更新日期:2009-09-01 00:00:00
abstract:OBJECTIVE:Effective endogenous fibrinolysis requires rapid release of endothelial tissue plasminogen activator (t-PA). Using the nitric oxide synthase inhibitor, L-NG-monomethylarginine (L-NMMA), we examined the contribution of endogenous nitric oxide to substance P-induced t-PA release in vivo in man. METHODS:Blood f...
journal_title:Cardiovascular research
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0008-6363(98)00017-0
更新日期:1998-05-01 00:00:00
abstract:OBJECTIVE:Important physiological and pathophysiological conditions are associated with changes in secretion and synthesis of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). The aim of this study was to examine the effects of mechanical stretch and endothelin-1 on ANF and BNP secretion and gene exp...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/28.10.1519
更新日期:1994-10-01 00:00:00
abstract:OBJECTIVES:Collagen synthesis is one of the major mechanisms of primary atherosclerotic plaque growth and is likely to be similarly important in restenosis. The patterns of collagen gene expression in human restenosis and associations with thrombosis/hemorrhage have not been described. METHODS:Using human coronary art...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::The theoretical possibilities and the practical limitations of the Xenon-133 (133Xe) method for the study of regional myocardial perfusion in man are discussed. The techniques for data acqusition and processing developed over the past 5 years are described in detail. Illustrative examples of experimental findings are ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/11.4.277
更新日期:1977-07-01 00:00:00
abstract::Electrophysiologic remodeling is a process whereby heart disease alters the electrophysiologic properties of cardiac tissue. These alterations, in turn, can cause or exacerbate disease-related arrhythmias. Ion channels are the fundamental molecular units underlying cardiac electrophysiology, and it therefore follows t...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/s0008-6363(99)00063-2
更新日期:1999-05-01 00:00:00
abstract:AIMS:Herpes virus entry mediator (HVEM) is considered to be a molecular 'switch' for immune responses, and a role in immune modification has been reported. The aim of this study was to assess whether HVEM-mediated immune suppression could protect against experimental autoimmune myocarditis (EAM) induced by myosin. MET...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvp219
更新日期:2009-12-01 00:00:00
abstract:OBJECTIVE:Automatic analysis of the frequency content of the fibrillatory baseline on the surface ECG accurately reflects the average rate of atrial fibrillation (AF). This frequency measurement correlates with the behavior of AF and predicts the response to administration of ibutilide, a new antiarrhythmic drug. Neith...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(99)00156-x
更新日期:1999-10-01 00:00:00
abstract:AIMS:Hypercholesterolaemia and myeloperoxidase (MPO) overexpression are two well-recognized risk factors for ischaemic heart disease. Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have recently been shown to reduce ischaemic heart injury in hypercholesterolaemic animals. However, whether PPARgam...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvn308
更新日期:2009-02-01 00:00:00
abstract::The effects of repeated (10 X), brief Ca2+-free perfusions (20 to 120 s) on myocardial contractility, coronary flow and release of cellular constituents of isolated rat heart were investigated. Ten successive Ca2+-deprivations of 20 or 40 s had no irreversible influences on cardiac performance. Ca2+-deprivations, howe...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/17.8.476
更新日期:1983-08-01 00:00:00
abstract:AIMS:Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with aging in HFrEF potentially leading to targeted therapies in this vulnerable...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvaa279
更新日期:2020-10-01 00:00:00
abstract::Chemokines, originally discovered as mediators of directional migration of immune cells to sites of inflammation and injury, have a function beyond their role in leukocyte chemotaxis. Indeed, they participate in organ development, angiogenesis, tumourigenesis and, more importantly, in the immune response. The chemokin...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvn029
更新日期:2008-05-01 00:00:00
abstract::Diabetic cardiomyopathy is a term used to describe cardiac muscle damage-induced heart failure. Multiple structural and biochemical reasons have been suggested to induce this disorder. The most prominent feature of the diabetic myocardium is attenuated insulin signalling that reduces survival kinases (Akt), potentiall...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvs426
更新日期:2013-03-01 00:00:00
abstract::Stroke, ischaemic stroke and subtypes of ischaemic stroke display substantial heritability. When compared with related vascular conditions, the number of established risk loci reaching genome-wide significance for association with stroke is still in the lower range, particularly for aetiological stroke subtypes such a...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvy068
更新日期:2018-07-15 00:00:00
abstract:Aims:Fibroblast growth factor 1 (FGF1), a heparin/heparan sulfate-binding growth factor, is a potent cardioprotective agent against myocardial infarction (MI). The impact of heparin, the standard of care for MI patients entering the emergency room, on cardioprotective effects of FGF1 is unknown, however. Methods and r...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvx165
更新日期:2017-11-01 00:00:00
abstract:BACKGROUND:Nitric oxide (NO) attenuates neutrophil (PMN)-mediated damage, partly by inhibiting superoxide anion (O2-) generation and adherence to the coronary artery endothelium. L-Arginine is the endogenous substrate for production of NO via the NO synthase pathway. This study tested the hypothesis that the endogenous...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1996-01-01 00:00:00
abstract:OBJECTIVE:This study was conducted to evaluate to what extent the ischemia-reperfusion injury resulting from the cardiopulmonary bypass (CPB) and aortic cross-clamping procedures during coronary artery bypass grafting (CABG) contributes to the systemic inflammatory response generally found in these patients. METHODS:S...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(99)00403-4
更新日期:2000-03-01 00:00:00
abstract:AIMS:This study examines the effect of endogenous male sex hormones on thromboxane A2 (TXA2), prostaglandin (PG) I2, PGF(2 alpha), and PGE I2 release, as well as their role in acetylcholine (ACh)-mediated relaxation in the aorta. METHODS AND RESULTS:Aortic segments from orchidectomized and control male Sprague-Dawley ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvm059
更新日期:2008-02-01 00:00:00
abstract:AIMS:The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with f...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvw233
更新日期:2017-01-01 00:00:00
abstract::Cardiomyocyte death secondary to transient ischaemia occurs mainly during the first minutes of reperfusion in the form of contraction band necrosis. Research on the mechanisms leading to sarcolemmal rupture and necrosis during initial reperfusion identified several promising pharmacological targets directed either to ...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvp109
更新日期:2009-07-15 00:00:00
abstract:OBJECTIVES:Epidemiological evidence in humans suggests that intrauterine growth retardation is associated with an increased risk of hypertension and coronary heart disease in later life. To begin to understand the mechanisms involved, we developed and exploited a rat model of intrauterine growth retardation to assess p...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(00)00167-x
更新日期:2000-11-01 00:00:00
abstract:OBJECTIVE:Evidence suggests important relationships among chronic inflammatory processes, endothelial dysfunction, hypertension and target organ damage. The present study examined the effects of chronic treatment with an anti-inflammatory p38 mitogen-activated protein kinase (MAPK) inhibitor (SB-239063AN) in the N(omeg...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2004.12.021
更新日期:2005-04-01 00:00:00
abstract:OBJECTIVE:The pulmonary circulation may contribute to elevated plasma levels of endothelin-1 (ET-1) in congestive heart failure (CHF). The aims of the present study were to determine the mechanisms of increased secretion of ET-1 from the pulmonary circulation in CHF. METHODS:Juvenile pigs were subjected to sham operat...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2004.03.016
更新日期:2004-07-01 00:00:00
abstract:AIMS:Human congenital heart disease linked to mutations in the homeobox transcription factor, NKX2-5, is characterized by cardiac anomalies, including atrial and ventricular septal defects as well as conduction and occasional defects in contractility. In the mouse, homozygous germline deletion of Nkx2-5 gene results in...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvr037
更新日期:2011-07-15 00:00:00
abstract:OBJECTIVE:Angiotensin II (ANG II) has recently been reported to increase inotropy in adult rabbit myocytes by a mechanism of alkalinization and consequent increased myofilament sensitivity to calcium. Accordingly, we tested the hypothesis that ANG II would have a greater inotropic effect during ischemic conditions than...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(96)00185-x
更新日期:1997-01-01 00:00:00
abstract:AIMS:To determine the role of gap junctions (GJs) in hypoxic pulmonary vasoconstriction (HPV). METHODS AND RESULTS:Studies were performed in rat isolated intrapulmonary arteries (IPAs) mounted on a myograph and in anaesthetized rats. Hypoxia induced a biphasic HPV response in IPAs preconstricted with prostaglandin F2α...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvt129
更新日期:2013-08-01 00:00:00
abstract:OBJECTIVE:Air bubbles entering the coronary artery may have harmful effects on cardiac function. From the physical point of view it is the relatively high surface tension of the blood-air interface which causes bubbles to trap in small vessels. The aim of the present study was to reduce depression of myocardial functio...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00063-1
更新日期:1997-06-01 00:00:00