ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Nitric oxide (NO) was originally discovered as a vasodilator product of the endothelium. Over the last 15 years, this vascular mediator has been shown to have important antiplatelet actions as well. By activating guanylyl cyclase, inhibiting phosphoinositide 3-kinase, impairing capacitative calcium influx, and inhibiting cyclooxygenase-1, endothelial NO limits platelet activation, adhesion, and aggregation. Platelets are also an important source of NO, and this platelet-derived NO pool limits recruitment of platelets to the platelet-rich thrombus. A deficiency of bioactive NO is associated with arterial thrombosis in animal models, individuals with endothelial dysfunction, and patients with a deficiency of the extracellular antioxidant enzyme glutathione peroxidase-3. This enzyme catalyzes the reduction of hydrogen and lipid peroxides, which limits the availability of these reactive oxygen species to react with and inactivate NO. The complex biochemical reactions that underlie the function and inactivation of NO in the vasculature represent an important set of targets for therapeutic intervention for the prevention and treatment of arterial thrombotic disorders.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The development of proteomics is a timely one for cardiovascular research. Analyses at the organ, subcellular, and molecular levels have revealed dynamic, complex, and subtle intracellular processes associated with heart and vascular disease. The power and flexibility of proteomic analyses, which facilitate protein separation, identification, and characterization, should hasten our understanding of these processes at the protein level. Properly applied, proteomics provides researchers with cellular protein “inventories” at specific moments in time, making it ideal for documenting protein modification due to a particular disease, condition, or treatment. This is accomplished through the establishment of species- and tissue-specific protein databases, providing a foundation for subsequent proteomic studies. Evolution of proteomic techniques has permitted more thorough investigation into molecular mechanisms underlying cardiovascular disease, facilitating identification not only of modified proteins but also of the nature of their modification. Continued development should lead to functional proteomic studies, in which identification of protein modification, in conjunction with functional data from established biochemical and physiological methods, has the ability to further our understanding of the interplay between proteome change and cardiovascular disease.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Abstract—The small G protein Rho and its target Rho-kinase may participate in the mechanisms underlying vascular contractile tone via inhibition of myosin light chain phosphatase. The present study has tested the hypothesis that Rho-kinase activity normally contributes to cerebral vascular tone in vivo, and that this effect is augmented during chronic hypertension. Comparative studies also examined the role of protein kinase C (PKC) in regulation of cerebral artery tone. Two Rho-kinase inhibitors, Y-27632 (0.1 to 100 &mgr;mol/L) and HA1077 (1 to 10 &mgr;mol/L), caused marked concentration-dependent increases in basilar artery diameter of anesthetized normotensive rats (Sprague-Dawley and Wistar-Kyoto [WKY] strains), as measured using a cranial window approach. By comparison, the selective PKC inhibitors calphostin C (0.01 to 0.5 &mgr;mol/L) and Ro 31-8220 (5 &mgr;mol/L) had little or no effect on basilar artery diameter. Vasodilator responses to Y-27632 were unaffected by PKC inhibition or activation. In two models of chronic hypertension (spontaneously hypertensive rats and WKY rats treated withN-nitro-l-arginine methyl ester for 4 weeks), Y-27632 elicited cerebral vasodilator responses that were significantly greater than in control WKY rats (P<0.05), indicating that the chronically hypertensive state and not genetic factors contributed to the increased responses to Rho-kinase inhibition. PKC inhibition had no significant effect on basilar artery diameter in chronically hypertensive rats. These data suggest that Rho-kinase, but not PKC, activity contributes substantially to cerebral artery tone in vivo, and this effect is augmented in the cerebral circulation during chronic hypertension.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Abstract—Cell proliferation and cell death (either necrosis or apoptosis) are key processes in the progression of atherosclerosis. The tumor suppressor gene p53 is an essential gene in cell proliferation and cell death and is upregulated in human atherosclerotic plaques, both in smooth muscle cells and in macrophages. In the present study, we investigated the importance of macrophage p53 in the progression of atherosclerosis using bone marrow transplantation in APOE*3-Leiden transgenic mice, an animal model for human-like atherosclerosis. APOE*3-Leiden mice were lethally irradiated and reconstituted with bone marrow derived from either p53-deficient (p53−/−) or control (p53+/+) donor mice. Reconstitution of mice withp53−/−bone marrow did not result in any hemopoietic abnormalities as compared withp53+/+transplanted mice. After 12 weeks on an atherogenic diet, APOE*3-Leiden mice reconstituted withp53−/−bone marrow showed a significant (P=0.006) 2.3-fold increase in total atherosclerotic lesion area as compared with mice reconstituted withp53+/+bone marrow. Although likely a secondary effect of the increased lesion area,p53−/−transplanted mice also showed significantly more lesion necrosis (necrotic index, 1.1±1.3 versus 0.2±0.7;P=0.04) and lesion macrophages (macrophage area, 79.9±40.0 versus 39.7±27.3×103&mgr;m2per section;P=0.02). These observations coincided with a tendency toward decreased apoptosis (terminal deoxynucleotidyl transferase end-labeling [TUNEL]–positive nuclei going from 0.42±0.39 to 0.14±0.15%,P=0.071), whereas the number of proliferating cells (5′-bromo-2′-deoxyuridine–positive nuclei) was not affected (3.75±0.98 versus 4.77±2.30%;P=0.59). These studies indicate that macrophage p53 is important in suppressing the progression of atherosclerosis and identify a novel therapeutic target for regulating plaque stability.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Abstract—Angiotensin II (Ang II) increases renal sympathetic nerve activity in anesthetized mice before and after ganglionic blockade, suggesting that Ang II may directly activate postganglionic sympathetic neurons. The present study directly tested this hypothesis in vitro. Neurons were dissociated from aortic-renal and celiac ganglia of C57BL/6J mice. Cytosolic Ca2+concentration ([Ca2+]i) was measured with ratio imaging using fura 2. Ang II increased [Ca2+]iin a subpopulation of sympathetic neurons. At a concentration of 200 nmol/L, 14 (67%) of 21 neurons responded with a rise in [Ca2+]i. The Ang II type 1 (AT1) receptor blocker (losartan, 2 &mgr;mol/L) but not the Ang II type 2 (AT2) receptor blocker (PD123,319, 4 &mgr;mol/L) blocked this effect. The Ang II–induced [Ca2+]iincrease was abolished by removal of extracellular Ca2+but not altered by depletion of intracellular Ca2+stores with thapsigargin. Ang II no longer elicited a [Ca2+]iincrease in the presence of lanthanum (25 &mgr;mol/L). The specific N-type and L-type Ca2+channel blockers, &ohgr;-conotoxin GVIA and nifedipine, respectively, significantly inhibited the Ang II–induced [Ca2+]iincrease. The protein kinase C inhibitor H7 but not the protein kinase A inhibitor H89 blocked the response to Ang II. These results demonstrate that Ang II selectively activates a subpopulation of postganglionic sympathetic neurons in aortic-renal and celiac ganglia, triggering Ca2+influx through voltage-gated Ca2+channels. This effect is mediated through AT1receptors and requires the activation of protein kinase C. The activation of a subgroup of sympathetic neurons by Ang II may exert unique effects on kidney function in pathological states associated with elevated Ang II.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Abstract—To elucidate microscopic mechanisms underlying the modulation of cardiac excitation-contraction (EC) coupling by &bgr;-adrenergic receptor (&bgr;-AR) stimulation, we examined local Ca2+release function, ie, Ca2+spikes at individual transverse tubule–sarcoplasmic reticulum (T-SR) junctions, using confocal microscopy and our recently developed technique for release flux measurement. &bgr;-AR stimulation by norepinephrine plus an &agr;1-adrenergic blocker, prazosin, increased the amplitude of SR Ca2+release flux (JSR), its running integral (∫JSR), and L-type Ca2+channel current (ICa), and it shifted their bell-shaped voltage dependence leftward by ≈10 mV, with the relative effects rankingICa> JSR>∫JSR. Confocal imaging revealed that the bell-shaped voltage dependence of SR Ca2+release is attributable to a graded recruitment of T-SR junctions as well as to changes in Ca2+spike amplitudes. &bgr;-AR stimulation increased the fractional T-SR junctions that fired Ca2+spikes and augmented Ca2+spike amplitudes, without altering the SR Ca2+load, suggesting that more release units were activated synchronously among and within T-SR junctions. Moreover, &bgr;-AR stimulation decreased the latency and temporal dispersion of Ca2+spike occurrence at a given voltage, delivering most of the Ca2+at the onset of depolarization rather than spreading it out throughout depolarization. Because the synchrony of Ca2+spikes affects Ca2+delivery per unit of time to contractile myofilaments, and because the myofilaments display a steep Ca2+dependence, our data suggest that synchronization of SR Ca2+release represents a heretofore unappreciated mechanism of &bgr;-AR modulation of cardiac inotropy.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Diazoxide, a selective opener of the mitochondrial ATP-sensitive potassium channel, has been shown to elicit tolerance to ischemia in cardiac myocytes and in perfused heart. However, the mechanism of this cardioprotection is poorly understood. Because reactive oxygen species (ROS) are recognized as important intracellular signaling molecules and have been implicated in ischemic preconditioning, we examined diazoxide-induced ROS production in adult cardiomyocytes. Cells treated with 50 &mgr;mol/L diazoxide showed a 173% increase in ROS production relative to baseline. 5-Hydroxydecanoate was found to attenuate the diazoxide-induced increase in ROS generation. The diazoxide-induced increase in ROS also was abrogated by the addition of either the antioxidantN-acetylcysteine (NAC) orN-mercaptopropionylglycine. We also examined the ability of NAC to block the protective effects of diazoxide in the perfused rat heart. After 20 minutes of global ischemia and 20 minutes of reflow, hearts perfused with 100 &mgr;mol/L diazoxide before ischemia showed significantly improved postischemic contractile function relative to untreated hearts (84% versus 29% of initial left ventricular developed pressure, respectively). Hearts treated with diazoxide in the presence of 4 mmol/L NAC recovered 53% of initial left ventricular developed pressure, whereas hearts treated with NAC alone recovered 46% of preischemic function. Using31P NMR spectroscopy, we found that, similar to preconditioning, diazoxide significantly attenuated ischemia-induced intracellular acidification and enhanced post-ischemic recovery of phosphocreatine levels, both of which were blocked by cotreatment with NAC. These data suggest that the cardioprotective actions of diazoxide are mediated by generation of a pro-oxidant environment.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID