摘要:

Background—Vascular restenosis attributable to intimal thickening remains a major problem after percutaneous transluminal coronary angioplasty (PTCA).Methods and Results—Through differential-display analysis, we have identified a novel gene whose expression was increased after catheter injury of rabbit aorta. The gene that is expressed predominantly in vascular smooth muscle cells encodes a novel protein with 7 transmembrane domains, and we termed itITR(intimal thickness–related receptor). TheITRsequence contains a motif common to the Rhodopsin-like GPCR (G-protein-coupled receptor) superfamily. In vivo analyses of this gene revealed that expression of ITR protein increased with intimal thickening induced by cuff placement around murine femoral artery. Furthermore,ITR-knockout mice were found to be resistant to this experimental intimal thickening.Conclusions—ITRthus seems to be a novel receptor that may play a role in vascular remodeling and that may represent a good target for development of drugs in the prevention of vascular restenosis.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—Interleukin (IL)-6 regulates various aspects of the immune response. In the context of heart diseases, it has been recognized as a prognostic factor for dilated cardiomyopathy, which often results from myocarditis.Methods and Results—Using IL-6–deficient mice, we studied the role of IL-6 in a model of autoimmune myocarditis resulting from immunization with a peptide derived from cardiac &agr;-myosin. Prevalence and severity of myocarditis were markedly reduced in the absence of IL-6. CD4+T cells from immunized IL-6–deficient mice proliferated poorly on restimulation with specific antigen in vitro and did not mediate disease on adoptive transfer into IL-6–competent RAG-2–deficient mice, which otherwise lack B cells and T cells. Production of complement C3, a crucial factor for the development of myocarditis, was strongly upregulated in IL-6+/+but not in IL-6–deficient mice after immunization.Conclusions—Our results demonstrate that IL-6 is required for the expansion of autoimmune CD4+T cells and the pathogenesis of autoimmune myocarditis, possibly by upregulation of complement C3.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—This study examines the quantitative accuracy, detection sensitivity, and time course of imaging the expression of a mutant herpes simplex type-1 virus thymidine kinase (HSV1-sr39tk) PET reporter gene in rat myocardium by using the PET reporter probe 9-(4-[18F]-Fluoro-3-Hydroxymethylbutyl)-Guanine ([18F]-FHBG) and a small-animal PET (microPET).Methods and Results—In 40 rats, adenovirus expressing HSV1-sr39tk driven by a cytomegalovirus promoter (Ad-CMV-HSV1-sr39tk, 1×106to 1×109pfu) was injected through a thoracotomy directly into the left ventricular myocardium. After 3 days, myocardial perfusion was imaged with [13N]-ammonia for delineating the left ventricular myocardium, followed by imaging the expression of the reporter gene with intravenous [18F]-FHBG. The total myocardial [18F]-FHBG accumulation was quantified in percent of injected dose (%ID). Immunohistochemistry and autoradiography demonstrated HSV1-sr39tk enzyme (HSV1-sr39TK) and accumulation of [18F]-FHBG in the inoculated myocardium in 3 rats each. In 24 rats with various viral titers, the %ID was correlated with ex vivo well counting (r2=0.981,P<0.0001) and myocardial HSV1-sr39TK activity by tissue enzyme activity assay (r2=0.790,P<0.0001). Myocardial [18F]-FHBG accumulation was identified at viral titers down to 1×107pfu. In 6 rats serially imaged up to day 17, myocardial [18F]-FHBG accumulation on microPET peaked on days 3 to 5 and was no longer identified on days 10 to 17.Conclusions—HSV1-sr39tk reporter gene expression can be monitored with [18F]-FHBG and microPET in rat myocardium quantitatively and serially with high detection sensitivity. Cardiac PET reporter gene imaging offers the potential of monitoring the expression of therapeutic genes in cardiac gene therapy.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—The tissue inhibitor of metalloproteinases-1 (TIMP-1) is expressed in atherosclerotic lesions, where it may play a critical role in regulating the activity of matrix metalloproteinases (MMPs). Several MMPs are overexpressed in the atherosclerotic plaque, and they are believed to contribute to the expansion and rupture of the lesion.Methods and Results—TheTimp-1–knockout mouse model (Timp-1−/−) was crossed into the apolipoprotein E–knockout (apoE0) background. A study population of male apoE0 mice, half of them deficient in TIMP-1, was fed an atherogenic diet. After 10 weeks of the diet, the mean lesion sizes of the two groups of animals were not significantly different, and the average content of fibrillar collagen and macrophages in the lesions was similar. There was no sign of plaque hemorrhage, even after 22 weeks of high-fat diet, indicating that deficiency in TIMP-1 does not predispose to luminal rupture. However the atherosclerotic lesions of theTimp-1−/0mice developed more aortic medial ruptures, in which all elastic lamellae of the media were degraded and infiltrated with macrophages, forming pseudo-microaneurysms. After 10 weeks of high-fat diet, theTimp-1−/0/apoE0 mice averaged 1.9±1.2 medial ruptures in the proximal aorta, compared with 0.5±0.7 for the apoE0 controls (P<0.003). At the site of degradation, in situ zymography revealed that the gelatinolytic activity, mainly associated with macrophages, could be abolished by the addition of MMP inhibitors.Conclusions—These data strongly suggest that TIMP-1 plays a key role in preventing medial degradation associated with atherosclerosis through its ability to inhibit the MMPs that are involved in the disruption of the media.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—We demonstrated recently that heat shock (HS)–induced heat shock protein 70 (HSP70) expression in bilateral nucleus tractus solitarii (NTS), the terminal site in the brain stem for primary baroreceptor afferents, confers cardiovascular protection against heatstroke by potentiating baroreceptor reflex (BRR) response. This study evaluated the hypothesis that altered regulation of HSP70 expression may be associated with the heightened susceptibility to heatstroke during hypertension.Methods and Results—Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats anesthetized with propofol were used. Compared with WKY rats, significant induction in HSP70 or phosphorylation of heat shock factor 1 (HSF1), but not HSF2, in the NTS and potentiation of BRR response in SHR occurred earlier (4 versus 8 hours), reaching peak magnitude sooner (16 versus 24 hours), and declined more rapidly after a brief hyperthermic HS (42±0.5°C for 15 minutes). The protection conferred by HS against hypotension and bradycardia during the onset of heatstroke (45°C for 60 minutes), although effective, was less effective in SHR. Microinjection bilaterally into the NTS of the selective protein kinase A (PKA) inhibitor H-89 (100 pmol) or the selective PKC inhibitor calphostin C (100 pmol) significantly attenuated all of the above events induced in SHR by HS. However, only H-89 was effective in WKY rats.Conclusions—An altered temporal profile of HS-induced HSP70 expression or potentiation of BRR response by concurrent activation via both PKA and PKC pathways of phosphorylation of HSF1 in the NTS may be associated with greater susceptibility to heatstroke during hypertension.

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