摘要:

Background—Oxidized LDL (ox-LDL) accumulation in the atherosclerotic region may enhance plaque instability. Both accumulation of ox-LDL and expression of its lectin-like receptor, LOX-1, have been shown in atherosclerotic regions. This study was designed to examine the role of LOX-1 in the modulation of metalloproteinases (MMP-1 and MMP-3) in human coronary artery endothelial cells (HCAECs).Methods and Results—HCAECs were incubated with ox-LDL (10 to 80 &mgr;g/mL) for 1 to 24 hours. Ox-LDL increased the expression of MMP-1 (collagenase) and MMP-3 (stromelysin-1) in a concentration- and time-dependent manner. Ox-LDL also increased collagenase activity. Ox-LDL did not significantly affect the expression of tissue inhibitors of metalloproteinases. Native LDL had no effect on the expression of MMPs. The effects of ox-LDL were mediated by its endothelial receptor, LOX-1, because pretreatment of HCAECs with a blocking antibody to LOX-1 (JTX92, 10 &mgr;g/mL) prevented the expression of MMPs in response to ox-LDL (P<0.01). In parallel experiments, ox-LDL caused the activation of protein kinase C (PKC), which was inhibited by LOX-1 antibody. The PKC-&bgr; isoform played a critical role in the expression of MMPs, because the PKC-&bgr; inhibitor hispidin reduced ox-LDL-induced activation of PKC and the expression of MMPs. Other PKC subunits (&agr;, &ggr;, and &egr;) did not affect the expression of MMPs.Conclusions—These findings indicate that ox-LDL, via LOX-1 activation, modulates the expression and activity of MMPs in HCAECs. In this process, activation of the PKC-&bgr; subunit plays an important signaling role.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—A potential mechanism for left ventricular (LV) remodeling after myocardial infarction (MI) is activation of the matrix metalloproteinases (MMPs). This study examined the effects of MMP inhibition (MMPi) on regional LV geometry and MMP levels after MI.Methods and Results—In pigs instrumented with radiopaque markers to measure regional myocardial geometry, MI was created by ligating the obtuse marginals of the circumflex artery. In the first study, pigs were randomized to MMPi (n=7; PD166793, 20 mg · kg−1· d−1) or MI only (n=7) at 5 days after MI, and measurements were performed at 2 weeks. Regional MI areas were equivalent at randomization and were increased in the MI-only group at 2 weeks after MI compared with the MMPi group. In the second study, pigs randomized to MMPi (n=9) or MI only (n=8) were serially followed up for 8 weeks. At 8 weeks after MI, LV end-diastolic dimension was lower with MMPi than in the MI-only group (4.7±0.1 versus 5.1±0.1 cm,P<0.05). Regional MI area was reduced with MMPi at 8 weeks after MI (1.3±0.1 versus 1.7±0.1 cm2,P<0.05). MMPi reduced ex vivo MMP proteolytic activity. In the MI region, membrane-type MMP levels were normalized and levels of the endogenous tissue inhibitor of MMPs (TIMP-1) were increased compared with normal levels with MMPi. These effects were not observed in the MI-only group.Conclusions—MMPi attenuated the degree of post-MI LV dilation and expansion of the infarct during the late phase of MI healing. In addition, exogenous MMPi caused region-specific modulation of certain MMP and TIMP species.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—Acetylsalicylic acid (ASA) inhibits cell proliferation. This may be mediated by transforming growth factor-&bgr; (TGF-&bgr;). TGF-&bgr; directly stops cell proliferation, restrains cells in G0, and inhibits the uptake of platelet-derived growth factor and insulin-like growth factor. These effects are identical to those observed with ASA treatment.Methods and Results—We cultured rat thoracic aorta vascular smooth muscle cells and measured cytotoxicity, cell proliferation, cell cycle, transcription of TGF-&bgr;1, and concentration of TGF-&bgr;1in supernatant medium. ASA dose-dependently restrained cells in G0phase with no cytotoxic effect and inhibited cell proliferation by 30.86%. Anti–TGF-&bgr;1reversed this inhibition by 30.21%. However, ASA treatment decreased TGF-&bgr;1transcription and had no significant effect on TGF-&bgr;1concentration.Conclusions—TGF-&bgr; seems to play an important role in ASA-mediated inhibition of cell proliferation. Therefore, treatment with ASA prevents coronary disease not only by means of its antiplatelet properties but also by an important inhibition of plaque growth. This relationship between ASA and TGF-&bgr; explains many other effects, such as cancer chemoprevention, immunomodulation, and wound healing. The aim of this study was to demonstrate this link.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—Dahl salt-sensitive rats fed a high-salt diet develop compensated left ventricular hypertrophy followed by a transition to myocardial failure. We previously reported an increase in a troponin T isoform (TnT3) and a decrease in TnT phosphorylation in failing Dahl salt-sensitive rat hearts compared with low-salt controls. The present study was undertaken to determine whether the thin filament plays a role in depression of the contractile machinery in this model.Methods and Results—Native thin filaments (NTFs) were isolated intact from rats with compensated left ventricular hypertrophy and failing hearts and compared with age-matched controls. NTF velocity was measured as a function of free calcium in the in vitro motility assay. Maximal velocity was similar in all groups. However, NTFs from failing hearts demonstrated a reduction in calcium sensitivity compared with controls, as reflected in the pCa50(5.88±0.05 versus 6.22±0.05, respectively,P<0.001). No difference in thin-filament motility (pCa50, Vmax) was observed in rats with compensated left ventricular hypertrophy compared with controls. Protein kinase A treatment of NTFs from control and failing hearts had no effect on thin-filament calcium sensitivity. However, the endothelin receptor blocker bosentan prevented the reduction in thin-filament calcium sensitivity found in failing hearts.Conclusions—The thin filament is a key modulator of contractile performance in the transition to failure in the Dahl salt-sensitive rat model. The alteration in thin-filament function may be mediated by an endothelin-triggered pathway potentially affecting protein kinase C signaling.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Abstract—A paradoxical increase in mortality attributable to diabetes has occurred, particularly during the last decade, despite the overall decrease in mortality attributable to coronary artery disease in patients without diabetes. Insulin resistance with or without frank type 2 diabetes has emerged as a major determinant of accelerated coronary artery disease and its sequelae. The advent of insulin sensitizers enables clinicians to target treatment of insulin resistance, as well as hyperglycemia and dyslipidemia. The prevalence of diabetes in the United States is enormous and is increasing rapidly. Patients with diabetes respond less favorably to percutaneous coronary interventions and surgery compared with nondiabetic patients. These considerations led to the initiation of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. It is designed to determine whether treatment targeted to attenuate insulin resistance can arrest or retard progression of coronary artery disease compared with treatment targeted to the same level of glycemic control with an insulin-providing approach. It is designed also to determine whether early revascularization reduces mortality and morbidity in patients with type 2 diabetes whose cardiac symptoms are mild and stable. Despite challenges in study design and enrollment, intensive follow-up, and the long duration of follow-up planned, the questions being addressed are compelling and seem to merit the effort.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID