ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The present study assesses whether ranolazine increases left ventricular (LV) function without an increase in myocardial oxygen consumption (M&OV0312;o2) and thus improves LV mechanical efficiency in dogs with heart failure (HF). Ranolazine did not change M&OV0312;o2and LV mechanical efficiency increased (22.4±2.8% to 30.9±3.4% (P<0.05). In contrast, dobutamine significantly increased M&OV0312;o2and did not improve mechanical efficiency. Thus, short-term treatment with ranolazine improved LV function without an increase in M&OV0312;o2, resulting in an increased myocardial mechanical efficiency in dogs with HF.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—This review considers critically the evidence for the involvement of mediators of innate and acquired immunity in various stages of atherosclerosis. Rapidly mobilized arms of innate immunity, including phagocytic leukocytes, complement, and proinflammatory cytokines, contribute to atherogenesis. In addition, adaptive immunity, with its T cells, antibodies, and immunoregulatory cytokines, powerfully modulates disease activity and progression. Atherogenesis involves cross talk between and shared pathways involved in adaptive and innate immunity. Immune processes can influence the balance between cell proliferation and death, between synthetic and degradative processes, and between pro- and antithrombotic processes. Various established and emerging risk factors for atherosclerosis modulate aspects of immune responses, including lipoproteins and their modified products, vasoactive peptides, and infectious agents. As we fill in the molecular details, new potential targets for therapies will doubtless emerge.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—The presence of multiple receptors for disparate nucleotides on endothelial cells makes it unclear how the endothelium differentiates among these signals. We propose that endothelial P2Y receptors are organized into cholesterol-rich signaling domains, such as caveolae and respond to nucleotide agonists by mobilizing intracellular calcium. Treatment of endothelial cells with 5 mmol/L &bgr;-methyl-cyclodextrin prevents calcium release in response to the nucleotide receptor agonists 2-methylthio-ATP, ATP, ADP, and UTP, but not the kinin receptor agonist bradykinin, suggesting that depletion of membrane cholesterol disrupts signaling at P2Y receptors and that bradykinin receptors are not prelocalized to cholesterol microdomains in these cells. Direct measurement of cholesterol content after &bgr;-methyl-cyclodextrin treatment of aortic rings reveals a concentration-dependent depletion of cholesterol that parallels functional antagonism of P2Y-mediated relaxation. Nucleotide- and bradykinin-mediated relaxation is disrupted by 5 to 15 mmol/L &bgr; -methyl-cyclodextrin treatment or 1 to 10 &mgr;g/mL filipin III in a concentration-dependent fashion. Norepinephrine contracted aorta treated with A23187 relaxes in an endothelium-dependent fashion despite depletion of 84% of membrane-extractable cholesterol. These data indicate that in the basal state, P2Y receptors but not the kinin receptor may be compartmented to cholesterol-dependent signaling domains in guinea pig endothelium and that cholesterol-rich microdomains in these cells can respond to intracellular calcium in an agonist-specific manner. We suggest that the functional organization of cholesterol-rich signaling microdomains allows agonist-specific responses to increases in intracellular calcium and that this property may be a general phenomenon that permits cells to respond disparately to agonists that may signal through common calcium release pathways.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Chronic hypoxia increases endothelial nitric oxide synthase (eNOS) production of nitric oxide (·NO) and cardioprotection in neonatal rabbit hearts. However, the mechanism by which this occurs remains unclear. Recent studies suggest that heat shock protein 90 (hsp90) alters eNOS function. In the present study, we examined the role of hsp90 in eNOS-dependent cardioprotection in neonatal rabbit hearts. Chronic hypoxia increased recovery of postischemic left ventricular developed pressure (LVDP). Geldanamycin (GA), which inhibits hsp90 and increases oxidative stress, decreased functional recovery in normoxic and hypoxic hearts. To determine if a loss in ·NO, afforded by GA, decreased recovery, GA-treated hearts were perfused withS-nitrosoglutathione (GSNO) as a source of ·NO. GSNO increased recovery of postischemic LVDP in GA-treated normoxic and hypoxic hearts to baseline levels. Although chronic hypoxia decreased phosphorylated eNOS (S1177) levels by ≈4- to 5-fold and total Akt and phosphorylated Akt by 4- and 5-fold, it also increased hsp90 association with eNOS by more than 3-fold. Using hydroethidine (HEt), a fluorescent probe for superoxide, we found that hypoxic hearts contained less ethidine (Et) staining than normoxic hearts. Normoxic hearts generated 3 times more superoxide by anN&ohgr;-nitro-l-arginine methyl ester (L-NAME)-inhibitable mechanism than hypoxic hearts. Taken together, these data indicate that the association of hsp90 with eNOS is important for increasing ·NO production and limiting eNOS-dependent superoxide anion generation. Such changes in eNOS function appear to play a critical role in protecting the myocardium against ischemic injury.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Local expression of tumor necrosis factor-&agr; (TNF-&agr;) at the sites of arterial injury after balloon angioplasty, suppresses endothelial cell (EC) proliferation and negatively affects reendothelialization of the injured vessel. We have previously reported that in vitro exposure of ECs to TNF-&agr; induced EC growth arrest and apoptosis. These effects were mediated, at least in part, by downregulation of cell cycle regulatory proteins. In the present study, we report potential mechanism(s) for TNF-&agr;–mediated suppression of cyclin A in ECs. TNF-&agr; exposure to ECs completely abrogated cyclin A mRNA expression via mechanisms involving both transcriptional and posttranscriptional modifications. TNF-&agr; inhibited de novo cyclin A mRNA synthesis and suppressed cyclin A promoter activity. Utilizing deletion mutants of human cyclin A promoter, we have identified CDE-CHR (Cell cycle–DependentElements–Cell cycle genesHomologyRegion) region of cyclin A promoter as a target for TNF-&agr; suppressive action. Experiments to investigate CDE-CHR binding proteins/factors revealed a TNF-&agr;–mediated increase in specific DNA binding activity to the CHR elements. This increase in binding activity by TNF-&agr; was mediated via the induction of a functionally novel 84-kDa protein that binds specifically to CHR in Southwestern assays. UV cross-linking and SDS-PAGE analysis of proteins eluted from specific complex confirmed the presence of this 84-kDa protein. Moreover, induction of this protein by TNF-&agr; was protein synthesis dependent. Additionally, exposure of ECs to TNF-&agr; markedly reduced cyclin A mRNA stability. Targeted disruption of this protein could potentially be a therapeutic strategy to rescue EC proliferation in vivo.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Detubulation of rat ventricular myocytes has been used to investigate the role of the t-tubules in Ca2+cycling during excitation-contraction coupling in rat ventricular myocytes. Ca2+was monitored using fluo-3 and confocal microscopy. In control myocytes, electrical stimulation caused a spatially uniform increase in intracellular [Ca2+] across the cell width. After detubulation, [Ca2+] rose initially at the cell periphery and then propagated into the center of the cell. Application of caffeine to control myocytes resulted in a rapid and uniform increase of intracellular [Ca2+]; the distribution and amplitude of this increase was the same in detubulated myocytes, although its decline was slower. On application of caffeine to control cells, there was a large, rapid, and transient rise in extracellular [Ca2+] as Ca2+was extruded from the cell; this rise was significantly smaller in detubulated cells, and the remaining increase was blocked by the sarcolemmal Ca2+ATPase inhibitor carboxyeosin. The treatment used to produce detubulation had no significant effect on Ca2+efflux in atrial cells, which lack t-tubules. Detubulation of ventricular myocytes also resulted in loss of Na+-Ca2+exchange current, although the density of the fast Na+current was unaltered. It is concluded that Na+-Ca2+exchange function, and hence Ca2+efflux by this mechanism, is concentrated in the t-tubules, and that the concentration of Ca2+flux pathways in the t-tubules is important in producing a uniform increase in intracellular Ca2+on stimulation.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Hypertrophied and failing cardiac myocytes generally show alterations in intracellular Ca2+handling associated with changes in the contractile function and arrhythmogenicity. The cardiac Na+-Ca2+exchange (NCX) is an important mechanism for Ca2+extrusion and cell relaxation. Its possible involvement in changes of excitation-contraction coupling (EC-coupling) with disease remains uncertain. We analyzed the NCX function in rat ventricular myocytes 5 to 6 months after experimental myocardial infarction (PMI) produced by left coronary artery ligation and from sham-operated (SO) hearts. Caged Ca2+was dialyzed into the cytoplasm via a patch-clamp pipette and Ca2+was released by flash photolysis to activate NCX and measure the associated currents (INaCa), whereas [Ca2+]ichanges were simultaneously recorded with a confocal microscope.INaCadensity normalized to the [Ca2+]ijumps was 2.6-fold higher in myocytes from PMI rats. The level of total NCX protein expression in PMI myocytes was also increased. Interestingly, although theINaCadensity in PMI cells was larger, PMI and SO myocytes presented virtually identical Ca2+transport via the NCX. This discrepancy was explained by a reduced surface/volume ratio (34.8%) observed in PMI cells. We conclude that the increase in NCX density may be a mechanism to maintain the required Ca2+extrusion from a larger cell to allow adequate relaxation.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID