摘要:

Several aspects of normal cardiovascular development require signaling by the vitamin A metabolite retinoic acid. We have previously established germ-line mutations in mice in the genes that encode the RAR alpha 1, RAR beta, and RXR alpha retinoic acid receptors as a means of studying the function of these receptors in vivo. Although mutation of RXR alpha results in fetal ventricular defects, the RAR alpha 1 and RAR beta mutations are apparently nonphenotypic in the heart and elsewhere. In this study, we have established and analyzed combinations of these receptor gene mutations. Malformations of the ventricular chamber (chamber hypoplasia and muscular ventricular septal defects), conotruncus (double-outlet right ventricle, transposition, and membranous ventricular septal defects), aortic sac (persistent truncus arteriosus and aorticopulmonary window), and aortic arch-derived arteries were recovered in various combinations of the RAR alpha 1, RAR beta, and RXR alpha gene mutations. Depending on the combination of receptor mutations, selective defects were obtained in specific cardiovascular compartments, suggestive of differential expression or function of each receptor within domains of the developing heart. (Circ Res. 1997;80:757-764.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The impedance to current flow in the intracellular compartment of guinea pig left ventricular myocardium was measured at 20 degrees C and 37 degrees C using tissue from hypertrophied hearts subjected to aortic constriction. Alternating current of varying frequency was passed longitudinally along myocardial preparations, which revealed two time constants: one attributed to the surface membrane at the ends of the preparation and a second lying in the intracellular pathway. The longitudinal impedance was quantitatively analyzed in terms of a parallel intracellular and extracellular pathway; the former had two series components, one attributable to the sarcoplasm and the other to the low-resistance junctions between adjacent cells. This interpretation was consistent (1) with control experiments using n-heptanol, which increased the component attributed to intercellular junctions but not sarcoplasmic resistivity, and (2) with suspensions of isolated myocytes, which yielded a similar value for the sarcoplasmic resistivity. Aortic constriction increased the heart weight-to-body weight ratio of experimental animals from a mean value of 3.10 +/- 0.28 to 5.05 +/- 0.83 g/kg after 50 days of constriction and 5.60 +/- 0.95 g/kg after 150 days of constriction. An increase of heart weight-to-body weight ratio at 150 days of constriction was associated with an increased intracellular resistivity, which could be attributed solely to an increase of the junctional resistance between adjacent cells by [nearly =]44% at 20 degrees C and 140% at 37 degrees C; the sarcoplasmic resistivity was unchanged. The results are discussed in terms of altered conduction in hypertrophied myocardium as a possible basis for arrhythmias in this tissue. (Circ Res. 1997;80:765-771.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Chronic atrial fibrillation is associated with a shortening of the atrial action potential duration and atrial refractory period. To test the hypothesis that these changes are mediated by changes in the density of specific atrial K sup + currents, we compared the density of K sup + currents in left and right atrial myocytes and the density of delayed rectifier K sup + channel alpha-subunit proteins (Kv1.5 and Kv2.1) in left and right atrial appendages from patients (n=28) in normal sinus rhythm with those from patients (n=15) in chronic atrial fibrillation (AF). Contrary to our expectations, nystatin-perforated patch recordings of whole-cell K sup + currents revealed significant reductions in both the inactivating (ITO) and sustained (IKsus) outward K sup + current densities in left and right atrial myocytes isolated from patients in chronic AF, relative to the ITOand IKsus50% in both the left and the right atrial appendages of AF patients. The finding that Kv1.5 expression is reduced in parallel with the reduction in delayed rectifier K sup + current density is consistent with recent suggestions that Kv1.5 underlies the major component of the delayed rectifier K sup + current in human atrial myocytes, the ultrarapid delayed rectifier K sup + current, IKur. The unexpected finding of reduced voltage-gated outward K sup + current densities in atrial myocytes from AF patients demonstrates the need to further examine the details of the electrophysiological remodeling that occurs during AF to enable more effective and safer therapeutic strategies to be developed. (Circ Res. 1997;80:772-781.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Two characteristic features of the rapid component of the cardiac delayed rectifier current (IKr) are prominent inward rectification and an unexpected reduction in activating current with decreased [K sup +]o. Similar features are observed with heterologous expression of HERG, the gene thought to encode the channel carrying IKr; moreover, recent studies indicate that the mechanism underlying rectification of HERG current is the inactivation that channels rapidly undergo during depolarizing pulses. The present studies were designed to determine the mechanism of IKrrectification and [K sup +]osensitivity in the mouse atrial myocyte cell line, AT-1 cells. Reducing [Mg2+]ito 0, which reverses inward rectification of some K sup + channels, did not alter IKrcurrent-voltage relationships, although it did decrease sensitivity to the IKrblockers dofetilide and quinidine 2- to 5-fold. To determine the presence and extent of fast inactivation of IKrin AT-1 cells, a brief hyperpolarizing pulse (20 ms to -120 mV) was applied during long depolarizations. Immediately after this pulse, a very large outward current that decayed rapidly to the previous activating current baseline was observed. This outward current component was blocked by the IKr-specific inhibitor dofetilide, indicating that it represented recovery from fast inactivation during the hyperpolarizing step, with fast reinactivation during the return to depolarized potential. With removal of inactivation using this approach, current-voltage relationships for IKr([K sup +]o, 1 to 20 mmol/L) were linear and reversed close to the predicted Nernst potential for K sup +. In addition, decreased [K sup +]odecreased the time constants for open [arrow right] inactivated and inactivated [arrow right] open transitions. Thus, in these cardiac myocytes, as with heterologously expressed HERG, IKrundergoes fast inactivation that determines its characteristic inward rectification. These studies demonstrate that the mechanism underlying decreased activating current observed at low [K sup +]ois more extensive fast inactivation.(Circ Res. 1997;80:782-789.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We tested the hypothesis that elevation of [Ca2+]iduring ischemic preconditioning (IPC) stimulates protein kinase C (PKC), which confers the protection against the ischemic injury. Langendorff-perfused rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion (I/R). In preconditioned groups, hearts were subjected to either IPC, consisting of 5-minute global ischemia and 10-minute reperfusion, or high-Ca2+ preconditioning (HCPC), ie, the 5-minute perfusion of higher Ca2+ perfusate (2.3 mmol/L Ca2+) followed by 10-minute perfusion of normal perfusate (1.8 mmol/L Ca2+), and then were subjected to I/R. A significant functional recovery and decreased lactate dehydrogenase release were observed in HCPC and IPC hearts compared with ischemic control hearts. ATP contents of preconditioned hearts were significantly higher than those of the ischemic control hearts. The cell structure in preconditioned hearts was preserved better than that in the ischemic control hearts. Furthermore, the activation and translocation of PKC from cytoplasm to sarcolemma were observed in the preconditioned hearts. Verapamil administered during IPC significantly attenuated the salutary effects of IPC. Administration of chelerythrine, a specific PKC inhibitor, completely abolished the HCPC- and IPC-induced cardioprotection. The translocation of PKC by IPC was blocked by verapamil or chelerythrine. Immunohistochemical study using rabbit polyclonal antibody against PKC isoforms indicated that stress induced by IPC or HCPC evoked the translocation of PKC alpha and PKC delta to the cell membrane. Translocation of PKC isoforms was attenuated by the treatment with verapamil or chelerythrine. These results demonstrate that (1) a transient increase in [Ca2+]iduring IPC is an important trigger for the activation of PKC, which is responsible for cardioprotection; (2) the elevation of [Ca2+]iduring IPC, at least partly, resulted from Ca2+ entry via voltage-dependent Ca2+ channel; and (3) activation and translocation of PKC alpha and PKC delta occur during IPC and HCPC and may be important in preconditioning.(Circ Res. 1997;80:790-799.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

To examine the cardioprotective role of A3adenosine receptors during myocardial ischemia/reperfusion injury, we tested the effect of N6-(3-iodobenzyl)adenosine-5 prime-N-methyluronamide (IB-MECA), a potent and selective A3adenosine receptor agonist, in models of myocardial stunning and infarction in chronically instrumented conscious rabbits. In phase I (studies of myocardial stunning), rabbits were subjected to six 4-minute coronary occlusions, each separated by 4-minute reperfusion periods, after which the recovery of systolic wall thickening was measured (ultrasonic crystals). In phase II (studies of myocardial infarction), rabbits were subjected to a 30-minute coronary occlusion followed by 3 days of reperfusion. In both phases, IB-MECA was administered as an intravenous bolus (100 micro g/kg) 10 minutes before the first coronary occlusion. This dose of IB-MECA was determined in pilot studies to have no effect on heart rate, arterial blood pressure, or plasma histamine concentration in rabbits. In phase I, IB-MECA markedly improved the recovery of wall thickening after the six occlusion/reperfusion cycles, and this effect was sustained throughout the 5-hour observation period; the total deficit of wall thickening (a measure of the overall severity of myocardial stunning) was reduced by 68% (control, 129 +/- 16 arbitrary units, n=7; IB-MECA, 41 +/- 6 arbitrary units, n=6; P<.01). The protective effects of IB-MECA against stunning were completely blocked by pretreatment with the nonselective adenosine receptor antagonist 8-p-sulfophenyl theophylline or the specific protein kinase C inhibitor chelerythrine. In phase II, IB-MECA reduced myocardial infarct size by 61%; infarct size (tetrazolium staining) was 41 +/- 4% of the risk region in control animals (n=8) and 16 +/- 6% in IB-MECA-treated animals (n=8, P<.01). These results demonstrate that in conscious rabbits the A3adenosine receptor agonist IB-MECA confers a powerful protection against both reversible (stunning) and irreversible (infarction) injury during acute myocardial ischemia and reperfusion by a protein kinase C-mediated pathway, suggesting that selective activation of A sub 3 receptors is an effective means of protecting the ischemic myocardium without hemodynamic changes. (Circ Res. 1997;80:800-809.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Leukocyte binding to the endothelium is one of the earliest events in the occurrence of atherosclerosis. Leukocyte adhesion molecules involved in this process have not been definitely identified. We have found that treatment of human aortic endothelial cells (HAECs) with minimally modified low-density lipoprotein (MM-LDL) for 24 hours caused a 2- to 3-fold increase of P-selectin protein, with little change in P-selectin surface expression. A 15-minute histamine treatment of cells exposed to MM-LDL caused a 50% to 100% increase in P-selectin surface expression compared with cells not treated with the lipoprotein. This increase resulted in a 2-fold increase in binding of leukocytes to the endothelium. Immunostaining of permeabilized HAECs after MM-LDL treatment also revealed a highly reproducible increase in intracellular P-selectin associated with rod-shaped structures, typical of Weibel-Palade bodies. Oxidized phospholipids were shown to be mainly responsible for the action of MM-LDL. This increased P-selectin expression was associated with MM-LDL-induced cAMP elevation. Like histamine, highly oxidized low-density lipoprotein, especially the oxidized fatty acids, caused immediate redistribution of P-selectin to the cell surface followed by reinternalization. Immunohistochemical staining showed that endothelial cells on human fatty streak lesions expressed increased levels of P-selectin compared with nonlesion areas. These studies suggest that P-selectin may play an important role in early recruitment of mononuclear cells to the subendothelium in human atherosclerosis and that oxidized lipoproteins may contribute to the increased expression of this molecule by increasing intracellular stores and causing redistribution to the cell surface. (Circ Res. 1997;80:810-818.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

4-fold (0.024 +/- 0.01 mV/min [control] versus 0.098 +/- 0.05 mV/min [LpL]). Under the same conditions, LpL increased LDL accumulation [nearly =]3-fold (0.016 +/- 0.003 mV/min [control] versus 0.047 +/- 0.013 mV/min [LpL]). Rapid efflux of LDL from the artery wall indicated that increased endothelial layer permeability was the primary mechanism during periods of increased lipolysis. Our data demonstrate two LpL-mediated effects that may increase the amount of LDL in the artery wall. These findings may pertain to the observed relationship between increased postprandial lipemia and atherosclerosis. (Circ Res. 1997;80:819-828.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Monocytes are activated during collateral artery growth in vivo, and monocyte chemotactic protein-1 (MCP-1) has been shown to be upregulated by shear stress in vitro. In order to investigate whether MCP-1 enhances collateral growth after femoral artery occlusion, 12 rabbits were randomly assigned to receive either MCP-1, PBS, or no local infusion via osmotic minipump. Seven days after occlusion, isolated hindlimbs were perfused with autologous blood at different pressures, measuring flows at maximal vasodilation via flow probe and radioactive microspheres, as well as peripheral pressures. This allowed the calculation of collateral (thigh) and peripheral (lower limb) conductances from pressure-flow tracings (slope of the curve). Collateral growth on postmortem angiograms was restricted to the thigh and was markedly enhanced with MCP-1 treatment. Both collateral and peripheral conductances were significantly elevated in animals with MCP-1 treatment compared with the control group, reaching values of nonoccluded hindlimbs after only 1 week of occlusion (collateral conductance, 70.6 +/- 19.23 versus 25.1 +/- 2.59 mL/min per 100 mm Hg; P<.01; peripheral conductance, 119.3 +/- 22.37 versus 45.4 +/- 6.80 mL/min per 100 mm Hg; P<.05). These results suggest that activation of monocytes plays an important role in collateral growth as well as in capillary sprouting. (Circ Res. 1997;80:829-837.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Thrombin has been implicated as an important mediator of vascular lesion formation in atherosclerosis and restenosis. To investigate a potential role for thrombin signaling in the vascular response to hypertension, we have studied thrombin receptor (TR) expression and regulation in hypertensive rats. Aortic TR mRNA was upregulated by angiotensin II (Ang II)-induced hypertension (10.7 +/- 2.5 times control, P<.02), which correlated with a 4-fold increase in thrombin-induced constriction in isolated endothelium-denuded aortic rings. The AT1receptor antagonist losartan normalized blood pressure and TR mRNA. Conversely, lowering blood pressure to the same degree with hydralazine did not abolish the upregulation of TR mRNA expression. When low-renin low-Ang II hypertension was induced in Dahl salt-sensitive rats, there was no detectable increase in the expression of aortic thrombin receptor mRNA. Finally, treatment with a chimeric heparin-binding form of the recombinant human Cu/Zn superoxide dismutase caused complete inhibition of TR mRNA upregulation, suggesting that an increased rate of superoxide anion production is an important signaling mechanism. Thus, increased TR expression via a redox-sensitive mechanism in the aortic smooth muscle of rats treated with Ang II represents a novel in vivo mechanism through which the hypertensive effects of Ang II are mediated. (Circ Res. 1997;80:838-844.)

ISSN:0009-7330    

出版商:OVID    

年代:1997

数据来源: OVID