Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Tissue edema is a facet of ischemia/reperfusion injury in many organs, polymorphonuclear leukocytes (PMN) presumably playing a contributory role. We studied the intracoronary adhesion of PMN and its effect on vascular permeability during reperfusion in isolated guinea-pig hearts. After a global ischemia of 15 min duration. PMN (10(7)) were infused into the coronary system during the first minute of reperfusion. PMN adhesion was measured as difference of applied PMN and those recovered in the effluent perfusate. Coronary permeability was assessed by measuring the rate of transudate formation (TF) on the epicardial surface, before as well as 5, 15 and 30 min after ischemia. Experiments were also performed in the presence of the NO-synthase inhibitor nitro-L-arginine (10 microM) and the ACE-inhibitor ramiprilat (2 microM), the latter known to enhance endogenous nitric oxide formation. Furthermore, the radical scavenger uric acid (0.5 mM) was applied either before and during ischemia or starting after PMN application. Ischemia/reperfusion increased coronary PMN adherence from 23 +/- 1% (basal) to 33 +/- 2%. Whereas ischemia alone did not influence TF (about 100 microliters/min during reperfusion), postischemic PMN infusion led to progressive TF. With nitro-L-arginine, PMN adhesion rose to 45 +/- 3%; TF increased to 212 +/- 30 microliters/min. In contrast, ramiprilat caused post-ischemic adhesion and TF to decline to basal values. In the presence of uric acid (UA) PMN adhesion declined to 26 +/- 2%, however, the subsequent increase in TF after withdrawal of UA was not markedly attenuated. On the other hand, infusion of UA after application of PMN caused a significant decrease of TF. The extracellular antioxidants SOD/catalase were without effect. As shown using luminol enhanced chemiluminescence. No was able to scavenge oxygen free radicals released by activated PMN. These findings indicate that enhanced PMN adhesion in reperfusion leads to an increase in coronary permeability. Scavenging of oxygen free radicals with NO or UA appears to mitigate both, postischemic PMN adhesion and PMN-induced vascular injury, even after adhesion.
J Mol Cell Cardiol 1996 Mar
PMID:Nitric oxide mitigates leukocyte adhesion and vascular leak after myocardial ischemia. 901 47

LV and myocyte function and angiotensin converting enzyme (ACE) activity with ACE inhibitor (ACEI) treatment were examined in four groups of dogs (n = 6 each): (1) control; (2) with 4 weeks of recovery from chronic rapid pacing (REC: 216 beats/min), (3) ACEI for the first 14 days of REC (ACEI--14), and (4) ACEI for 28 days of REC (ACEI--28). Three additional control dogs were administered ACEI for 28 days. LV mass increased with REC compared to control (146 +/- 6 v 92 +/- 3 g, P < 0.05), was unaffected with ACEI--14, and was decreased with ACEI--28 compared to REC (111 +/- 8 g, P < 0.05). Myocyte function was decreased in REC compared to controls (43 +/- 3 v 63 +/- 3 microns/s, P < 0.05) and was similarly reduced with ACEI--14. However, with ACEI--28, myocyte shortening velocity was increased compared to REC (56 +/- 1 microns/s, P < 0.05). Myocyte beta-adrenergic response was decreased with REC and ACEI--14 compared to controls (53 +/- 9 and 57 +/- 14, respectively v 127 +/- 14 microns/s, P < 0.05). ACEI--28 resulted in a normalization of myocyte beta-adrenergic responsiveness (108 +/- 3 microns/s). LV myocardial ACE activity increased in REC compared to control (5.82 +/- 0.21 v 3.51 +/- 0.15 nmol/mg/min, P < 0.05). With ACEI--14 or ACEI--28, myocardial ACE activity was decreased compared to REC (4.16 +/- 0.06 and 4.08 +/- 0.23 nmol/mg/min; P < 0.05). In control dogs administered ACEI, there were no differences in any of these parameters compared to controls. The unique findings in this study were: (1) effects of ACEI treatment in this model of LV hypertrophy were time dependent with respect to LV mass and LV and myocyte function; and (2) the effect of ACEI treatment on the degree of LV hypertrophy appears to not be solely due modulation of myocardial ACE activity.
J Mol Cell Cardiol 1997 Feb
PMID:Effects of chronic angiotensin-converting enzyme inhibition on left ventricular and myocyte structure and function during recovery from chronic rapid pacing. 914 Aug 27

The lack of efficient treatment for myocardial infarction remains an unresolved problem in the field of cardiovascular disease. Gene therapy may be a potential therapeutic strategy for the treatment of myocardial infarction. However, current methods of in vivo gene transfer into the heart are limited by their low efficiency and/or potential toxicity. In the present study, we developed an efficient technique of gene transfer into the intact heart in vivo using the Sendai virus (HVJ: Hemagglutinating Virus of Japan)--liposome method. We used the beta-galactosidase gene, luciferase gene and human angiotensin converting enzyme (ACE) gene as markers. In vivo gene transfer into the rat heart was performed as follows: (1) direct injection into the rat heart, (2) incubation within the pericardium, and (3) infusion into a coronary artery. Direct injection of the HVJ-liposome complex containing the beta-galactosidase vector into the rat heart resulted in limited staining of beta-galactosidase 3 days after transfection. To compare transfection efficiency between "naked" plasmid DNA transfection and the HVJ-liposome method, we also transfected the luciferase reporter gene into the heart. Luciferase activity was significantly higher in hearts transfected by the HVJ-liposome method than that in hearts transfected by direct "naked" plasmid transfection (P < 0.01). To confirm the successful gene in the protein level, we measured ACE activity in the hearts. Cardiac ACE activity was significantly increased in hearts transfected with human ACE gene as compared to hearts transfected with control vector (P < 0.01). On the other hand, incubation of HVJ-liposome complex, containing beta-galactosidase vector, within the pericardium resulted in widespread staining of cardiac myocytes and fibroblasts, mainly located in several surface layers beneath the pericardium. More importantly, widespread stained areas of beta-galactosidase were also observed in the middle of the myocardium around the vasa vasorum. We also examined the efficiency of gene transfer by the HVJ-liposome method in a rat myocardial infarction model. In the infarction model, using the pericardium incubation approach, staining for beta-galactosidase was observed in the viable cells around the infarction area. Finally, direct infusion of the HVJ complex, containing the beta-galactosidase vector, into coronary artery also resulted in widespread staining of beta-galactosidase in cardiac myocytes around the microvasculature. Using direct injection, we found significant injury to the myocardium and severe fibrosis at the injection site, whereas no apparent injury was observed using pericardium incubation and coronary infusion. There was no evidence of cytotoxicity or inflammation caused by the HVJ-liposome complex itself. Overall, we have established an efficient in vivo gene transfer method into the heart using the HVJ-liposome method. Direct infusion into the coronary artery resulted in widespread transfection without damaging the myocytes; incubation within the pericardium demonstrated the usefulness of the HVJ-liposome method for studying cardiac function and as a means of gene therapy for cardiovascular diseases.
J Mol Cell Cardiol 1997 Mar
PMID:Efficient in vivo gene transfer into the heart in the rat myocardial infarction model using the HVJ (Hemagglutinating Virus of Japan)--liposome method. 915 56

Scar tissue found at the site of myocardial infarction (MI) contains phenotypically transformed fibroblast-like cells termed myofibroblasts (myoFb). In injured cardiac tissue, autoradiography and immunolabeling have localized high density angiotensin (Ang) converting enzyme (ACE) and Ang II receptor binding to these cells, suggesting that they may regulate local concentrations of Ang II and transduce signals at this site. Ang II is known to modulate type I collagen gene expression of fibroblasts and myoFb, and to promote fibrous tissue contraction, each of which may contribute to tissue repair. It is unknown whether myoFb themselves generate Ang peptides de novo via expression of angiotensinogen (Ao), an aspartyl protease needed to convert Ao to Ang I, and ACE. We therefore isolated and cultured myoFb from 4-week-old scar tissue of the adult rat left ventricle with transmural MI. In cultured myoFb we found: (a) immunoreactive membrane-bound ACE, cytosolic cathepsin D (Cat-D), and AT, receptors by immunofluorescence and confocal microscopy, (b) mRNA expression for Ao, ACE, and Cat-D, but not renin, by reverse transcriptase-polymerase chain reaction, (c) production of Ang I and II in serum-free culture media; (d) absence of renin activity; (e) a time-dependent conversion of Ao to Ang I by myoFb cytosol, which was inhibited by pepstatin A, but not by renin inhibitor; and (f) significant increase in Ang II production (P < 0.05) by exogenous Ao and Ang I (10 nM), which was significantly blocked by lisinopril (0.1 microM: P < 0.05). Thus, cultured myoFb express requisite components and are able to generate Ang I and II de novo. In an autocrine and/or paracrine manner, Ang II may regulate myoFb collagen turnover and fibrous tissue contraction.
J Mol Cell Cardiol 1997 May
PMID:Cultured myofibroblasts generate angiotensin peptides de novo. 920 23

The objective of this study was to determine the effect of angiotensin I (Ang I) treatment in vivo on two major Ca-transport systems-the L-type voltage dependent calcium channel (L-VDCC) and the Na/Ca exchanger in rat heart. For our experiments we used four groups of rats, treated differently with saline, Ang I, the ACE inhibitor enalapril and/or combination of both for 6 days, every 24 h. We observed an increase in the activity, and also in mRNA expression of the Na/Ca exchanger, after repeated administration of Ang I in vivo. The maximal binding capacity of Ca-antagonist PN 200-110, which binds to the alpha 1 subunit of the L-VDCC was elevated from 0.8-1.85 pg/mg protein. mRNA expression of the voltage-dependent calcium channels of L-type system was also upregulated by Ang I administration, but not when enalapril was applied simultaneously with Ang I. These results demonstrate that in vivo application of the Ang I significantly modulates not only the activity, but also expression of the Na/Ca exchanger and the L-VDCC in rat hearts through angiotensin II (Ang II). Since in the in vitro experiments on the isolated cardiomyocytes, Ang II (100 nM) increased the calcium uptake after depolarization, and the AT1 receptor agonist losartan prevented this increase, we assume that this regulation might involve the AT1 receptors.
J Mol Cell Cardiol 1997 Jun
PMID:Angiotensin I modulates Ca-transport systems in the rat heart through angiotensin II. 922 Mar 59

Alacepril is an inhibitor of the angiotensin converting enzyme (ACE), and is commonly used as an antihypertensive. In this study, the effects of alacepril, its metabolites, desacetylalacepril and captopril, and also lisinopril, which has no sulfhydryl group in the structure, on free radicals were examined in vitro, using an ESR method. Superoxide and hydroxyl radical scavenging activities of alacepril metabolites, desacetylalacepril and captopril, were observed, whereas lisinopril hardly scavenged the superoxide or the hydroxyl radicals. Alacepril and its metabolites did not scavenge nitric oxide, but lisinopril showed slight scavenging activity. These findings suggest that the biological action of alacepril may be partly due to the antioxidant effect of its metabolites, having a sulfhydryl group.
Res Commun Mol Pathol Pharmacol 1997 May
PMID:Free radical scavenging properties of alacepril metabolites and lisinopril. 922 47

Plasmalemmal vesicles (PVs) or caveolae are plasma membrane invaginations and associated vesicles of regular size and shape found in most mammalian cell types. They are particularly numerous in the continuous endothelium of certain microvascular beds (e.g., heart, lung, and muscles) in which they have been identified as transcytotic vesicular carriers. Their chemistry and function have been extensively studied in the last years by various means, including several attempts to isolate them by cell fractionation from different cell types. The methods so far used rely on nonspecific physical parameters of the caveolae and their membrane (e.g., size-specific gravity and solubility in detergents) which do not rule out contamination from other membrane sources, especially the plasmalemma proper. We report here a different method for the isolation of PVs from plasmalemmal fragments obtained by a silica-coating procedure from the rat lung vasculature. The method includes sonication and flotation of a mixed vesicle fraction, as the first step, followed by specific immunoisolation of PVs on anticaveolin-coated magnetic microspheres, as the second step. The mixed vesicle fraction, is thereby resolved into a bound subfraction (B), which consists primarily of PVs or caveolae, and a nonbound subfraction (NB) enriched in vesicles derived from the plasmalemma proper. The results so far obtained indicate that some specific endothelial membrane proteins (e.g., thrombomodulin, functional thrombin receptor) are distributed about evenly between the B and NB subfractions, whereas others are restricted to the NB subfraction (e.g., angiotensin converting enzyme, podocalyxin). Glycoproteins distribute unevenly between the two subfractions and antigens involved in signal transduction [e.g., annexin II, protein kinase C alpha, the G alpha subunits of heterotrimeric G proteins (alpha s, alpha q, alpha i2, alpha i3), small GTP-binding proteins, endothelial nitric oxide synthase, and nonreceptor protein kinase c-src] are concentrated in the NB (plasmalemma proper-enriched) subfraction rather than in the caveolae of the B subfraction. Additional work should show whether discrepancies between our findings and those already recorded in the literature represent inadequate fractionation techniques or are accounted for by chemical differentiation of caveolae from one cell type to another.
Mol Biol Cell 1997 Apr
PMID:Immunoisolation and partial characterization of endothelial plasmalemmal vesicles (caveolae). 924 41

Hypertension is a significant risk factor for heart attack and stroke and represents a major public health burden because of its high prevalence (e.g. 15-20% of the European and American populations). Although blood pressure is known to have a strong genetic determination, the genes responsible for susceptibility to essential hypertension are mostly unknown. Loci involved in blood pressure regulation have been found by linkage in experimental hereditary hypertensive rat strains, but their relationship to human hypertension has not been extensively investigated. One of the principal blood pressure loci has been mapped to rat chromosome 10 and we have undertaken an investigation of the homologous region on human chromosome 17 in familial essential hypertension. Affected sib-pair analysis and parametric analysis with ascertainment correction gave significant evidence of linkage ( P <0.0001 in some analyses) near two closely linked microsatellite markers, D17S183 and D17S934, that reside 18 cM proximal to the ACE locus in the homology region. Our results indicate that chromosome 17q could contain a susceptibility locus for human hypertension and show that comparative mapping may be a useful approach for identification of such loci in humans.
Hum Mol Genet 1997 Nov
PMID:Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10. 932 71

New methods for docking, template fitting and building pseudo-receptors are described. Full conformational searches are carried out for flexible cyclic and acyclic molecules. QXP (quick explore) search algorithms are derived from the method of Monte Carlo perturbation with energy minimization in Cartesian space. An additional fast search step is introduced between the initial perturbation and energy minimization. The fast search produces approximate low-energy structures, which are likely to minimize to a low energy. For template fitting, QXP uses a superposition force field which automatically assigns short-range attractive forces to similar atoms in different molecules. The docking algorithms were evaluated using X-ray data for 12 protein-ligand complexes. The ligands had up to 24 rotatable bonds and ranged from highly polar to mostly nonpolar. Docking searches of the randomly disordered ligands gave rms differences between the lowest energy docked structure and the energy-minimized X-ray structure, of less than 0.76 A for 10 of the ligands. For all the ligands, the rms difference between the energy-minimized X-ray structure and the closest docked structure was less than 0.4 A, when parts of one of the molecules which are in the solvent were excluded from the rms calculation. Template fitting was tested using four ACE inhibitors. Three ACE templates have been previously published. A single run using QXP generated a series of templates which contained examples of each of the three. A pseudo-receptor, complementary to an ACE template, was built out of small molecules, such as pyrrole, cyclopentanone and propane. When individually energy minimized in the pseudo-receptor, each of the four ACE inhibitors moved with an rms of less than 0.25 A. After random perturbation, the inhibitors were docked into the pseudo-receptor. Each lowest energy docked structure matched the energy-minimized geometry with an rms of less than 0.08 A. Thus, the pseudo-receptor shows steric and chemical complementarity to all four molecules. The QXP program is reliable, easy to use and sufficiently rapid for routine application in structure-based drug design.
J Comput Aided Mol Des 1997 Jul
PMID:QXP: powerful, rapid computer algorithms for structure-based drug design. 933

Hypertrophied and failing myocardium has been shown to undergo creatine kinase (CK) isoform switching, resulting in increased MB and BB components. We tested the hypothesis that chronic volume overload hypertrophy due to mitral regurgitation in the dog causes CK isoenzyme switching and that this could be reversed by angiotensin converting enzyme inhibitor therapy. Thirteen adult mongrel dogs had mitral regurgitation induced by mitral valvular chordal rupture: six were treated with ramipril for 4 months and seven were untreated for 4 months. Twelve dogs were sham-operated: six received ramipril for 3 months and six were untreated. Left ventricular end-diastolic volume increased from 58+/-4 to 104+/-10 ml in untreated (P<0.001) and from 55+/-3 to 91+/-6 ml in treated dogs (P<0.01) as LV mass/volume ratio decreased in both untreated (1. 60+/-0.07 to 1.13+/-0.08 g/ml, P<0.001) and treated dogs (1.44+/-0.06 to 1.20+/-0.08 g/ml, P<0.01). CK-MB isoform was 7.4+/-1.1% in normal shams and increased to 13.5+/-1.9% and 18.1+/-3.0% in both treated and untreated mitral regurgitation dogs; respectively (P<0. 05). Steady state CK-B mRNA increased three-fold in treated and untreated dogs with mitral regurgitation (P<0.003) compared to normals, while CK-M mRNA expression did not differ in all groups. Thus, chronic volume overload hypertrophy of mitral regurgitation induces CK isoform switching by selective induction of the CK-B gene, and ramipril therapy does not affect this isoform switch. This may reflect a response to increased diastolic stress and more efficient energy utilization in the volume overloaded myocardium.
J Mol Cell Cardiol 1997 Oct
PMID:Selective induction of the creatine kinase-B gene in chronic volume overload hypertrophy is not affected by ACE-inhibitor therapy. 934 61


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