Biomedical subjects

Lilach O Lerman

Publications and source records attributed to Lilach O Lerman.

82 records · Page 5Linked to original sources

PubMed2002

Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering.

BACKGROUND: Previous studies have demonstrated that experimental hypercholesterolemia leads to neovascularization in the coronary artery vasa vasorum (VV). Recent evidence suggests that HMG-CoA reductase inhibitors (statins) have beneficial effects independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary VV neovascularization, in the absence of cholesterol lowering. METHODS AND RESULTS: Pigs were randomized to 3 groups fed a normal (N), high cholesterol (HC), or HC+simvastatin (HC+S) diet for 12 weeks. The proximal left anterior descending artery was isolated, scanned with micro-CT, and reconstructed. Quantification of the VV density in serial cross-sections along the vessel was then performed. LDL cholesterol was similarly increased in HC and HC+S compared with N. There was an increase in both VV density (4.7+/-0.3 versus 2.7+/-0.2 n/mm(2); P<0.05) and vessel wall area (3.1+/-0.2 versus 1.8+/-0.1 mm(2); P<0.05) in HC compared with N. The VV density in HC+S was preserved compared with HC (3.0+/-0.2 n/mm(2); P<0.05), despite similar increase in vessel wall area compared with N (2.5+/-0.1 mm(2); P<0.05). Coronary artery tissue expression of VEGF was increased in HC but not in HC+S compared with N. In parallel, immunoreactivity for HIF-1alpha, VEGF, MMP-2, and MMP-9 was accentuated in the outer media in HC but not in HC+S compared with N. CONCLUSIONS: This study demonstrates that simvastatin attenuates hypoxia in the coronary artery wall and VV neovascularization in experimental hypercholesterolemia, despite no change in plasma lipids. These data are consistent with an additional mechanism for the vascular effects of the statins, independent of cholesterol lowering.

Animals↗

PubMed2002

Chronic antioxidant supplementation attenuates nuclear factor-kappa B activation and preserves endothelial function in hypercholesterolemic pigs.

OBJECTIVE: Hypercholesterolemia (HC), a pro-oxidant condition, activates nuclear factor-kappa beta (NF-kappa B) and is associated with coronary endothelial dysfunction. The physiological significance of in vivo chronic antioxidant intervention on HC-induced NF-kappa B activation and coronary endothelial function remains unclear. METHODS: Four groups of pigs were studied after 12 weeks of normal diet, normal diet with concomitant antioxidant intervention (100 IU/kg of vitamin E and 1 g of vitamin C daily), 2% HC diet, or HC diet+antioxidant supplementation. NF-kappa B activation and the nitric oxide (NO) pathway were investigated by Western blotting and immunohistochemistry, while oxidative stress was evaluated by coronary artery tissue radical scavenger activity and levels of vitamin E and C. Endothelial function was studied in vitro by coronary vasoreactivity to bradykinin and substance P. RESULTS: HC animals had increased activation of NF-kappa B, decreased endothelial NO synthase expression, and decreased radical scavenger system activity, associated with impaired coronary endothelial function. Antioxidant supplementation in HC normalized NF-kappa B activation and NO bioactivity, and preserves coronary endothelial function. CONCLUSIONS: This study demonstrates for the first time that in vivo chronic interruption of the endogenous oxidative stress cascade reduces HC-induced NF-kappa B activation and normalizes NO bioactivity in association with preservation of coronary endothelial function. This study suggests a role for increased oxidative stress and NF-kappa B activation in early atherosclerosis.

Animals↗

PubMed2002

New insights in the transcriptional activity and coregulator molecules in the arterial wall.

A number of vascular diseases are associated with abnormal expression of genes that contribute to their pathophysiological and clinical manifestations, but at the same time offer potential therapeutic targets. One of the promising therapeutic approaches targets the pathophysiological pathways leading to aberrant gene activation, namely transcriptional activity and its molecular modulators (agonists, antagonists, coregulators, and nuclear receptors). The transcription factors can be divided into four classes (I-IV) classified by structural elements, like basic leucine zipper (bZIP) or basic helix-loop-helix (bHLH), which mediate their DNA binding activity but also determine the classes of drugs that can affect their activity. For example, statins modulate activation of the class-I transcription factor sterol responsive element-binding protein (SREBP), whose target genes including hydroxyl-methyl-glutaryl acetyl Coenzyme-A (HMG-CoA) reductase, HMG-CoA synthase, and the low-density lipoprotein receptor, all of which are involved in cholesterol and fatty acid metabolism. Similarly, insulin-like drugs target the nuclear receptor peroxisome-proliferator-activator-receptor (PPAR)-gamma (class-II), several anti-inflammatory drugs inhibit activation of nuclear factor kappa B (NFkappaB) (class-IV), while others (e.g. flavopiridol, rapamycin, and paclitaxel) target regulation of cell-cycle proteins. Increased understanding of the genetic and molecular basis of disease (e.g. transcriptional activity and its coregulation) will potentially enhance future diagnosis, treatment, and prevention of vascular diseases.

Arteries↗

PubMed2002

Enhanced renal cortical vascularization in experimental hypercholesterolemia.

BACKGROUND: Experimental hypercholesterolemia is associated with pro-inflammatory changes and impaired regulation of tissue perfusion, which may lead to neovascularization. However, it is yet unknown whether such changes take place in the kidney. In this study, using a novel three-dimensional (3-D) micro computed-tomography technique we tested the hypothesis that hypercholesterolemia was associated with increased microvascular density in the renal cortex. METHODS: Kidneys were excised from pigs after 12 weeks of either a normal (N = 6) or high cholesterol (HC; N = 5) diet, histology slides processed, and a segmental renal artery injected with a radio-opaque intravascular silicone polymer. Renal samples were scanned with micro computed-tomography, transverse and three-dimensional images were reconstructed, and microvessels (80 to 360 microm in diameter) counted in situ. RESULTS: Serum cholesterol levels were significantly higher in hypercholesterolemic compared to normal pigs (383 +/- 76 vs. 81 +/- 7 mg/dL, P < 0.01), and microvascular spatial density was significantly higher in their inner and middle renal cortex (189 +/- 7 vs. 126 +/- 6 microvessels/cm2, P < 0.0001). Hypercholesterolemic kidneys also showed mild interstitial mononuclear infiltration and heavier immunostaining of vascular endothelial growth factor, but no other signs of morphological damage. CONCLUSIONS: These results demonstrate that early diet-induced hypercholesterolemia is associated with increased microvascular density in the renal cortex, which precedes signs of overt renal morphological damage. These alterations may potentially affect regulation and/or spatial distribution of intrarenal blood flow in hypercholesterolemia, and may participate in renal disease progression.

Animals↗

PubMed2002

Quantification of myocardial microcirculatory function with X-ray CT.

A mathematical model of the intramyocardial coronary microcirculation is used to explore the validity of a fast CT imaging method for characterizing the myocardial microcirculatory functional status. The fast CT method depends on the demonstrated CT-based estimation of myocardial perfusion (F) and the intramyocardial blood volume (B(v)). The observed curvilinear myocardial blood volume-to-flow relationship, empirically fitted to B(v) = a.F + b.F(0.5), is a signature of the underlying early pathophysiologic processes thought to be involved in systemic disease processes, such as atherosclerosis, hypertension, and diabetes mellitus. The sensitivity and specificity of the CT-based estimate of this characteristic relationship is explored by altering the characteristics of the vascular diameter-to-flow relationship and the variation in the fraction of capillaries perfused at different coronary flows. The simulation results also indicate that if the vascular diameters change so that the vascular resistance corresponds to the change in flow, then the empirically observed myocardial B(v)-to-F relationship holds well.

Animals↗

PubMed2002

Renal handling of X-ray contrast media imaging and exploration with electron beam CT.

Physiologic changes in renal hemodynamics and function reflect its role as a regulatory organ in maintaining homeostasis, whereas other alterations may mirror development of renal injury and often precede overt signs of morphologic changes. Furthermore, intrarenal alterations may be discreet and manifest only in the renal cortical, medullary, or papillary zones. The high spatial and temporal resolution of electron-beam computed tomography enables external detection and quantification of cortical, medullary, and papillary tissue density changes following an intravenous bolus injection of X-ray contrast media. These changes reflect flow of contrast media in these renal zones through the successive renal vascular, glomerular, and tubular compartments that can be individually plotted as time-density curves (TDC). Mathematical modeling then allows calculation of unique parameters of renal function from these TDC. This ability to quantify renal regional attributes may not only shed light on the physiologic mechanisms that the kidney controls, but also assist in detecting subtle impairment in its function.

Contrast Media↗

PubMed2002

Vascular responses in vivo to 8-epi PGF(2alpha) in normal and hypercholesterolemic pigs.

Hypercholesterolemia (HC) is characterized by increased circulating 8-epi-prostaglandin-F(2alpha) (isoprostane), a vasoconstrictor, marker, and mediator of increased oxidative stress, whose vascular effects might be augmented in HC. Anesthetized pigs were studied in vivo with electron beam computed tomography after a 12-wk normal (n = 8) or HC (n = 8) diet. Mean arterial pressure (MAP), single-kidney perfusion, and glomerular filtration rate (GFR) were quantified before and during unilateral intrarenal infusions of U46619 (10 ng x kg(-1) x min(-1)) or isoprostane (1 microg x kg(-1) x min(-1)). Basal renal perfusion and function were similar, and isoprostane infusion elevated its systemic levels similarly in normal and HC (333 +/- 89 vs. 366 +/- 48 pg/ml, respectively, P < 0.01 vs. baseline). Both drugs markedly and comparably decreased cortical perfusion and GFR in both groups, whereas medullary perfusion decreased significantly only in HC. Moreover, MAP increased significantly only in HC (+9 +/- 3 and +11 +/- 3 mmHg, respectively, P<or= 0.05). Hence, in HC, renal functional responses to high-dose isoprostane are largely similar to normal, but the systemic circulation exhibits augmented sensitivity to pathophysiological levels of isoprostane and U46619, which may potentially play a role in development of hypertension and vascular injury associated with increased oxidative stress.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

Renal vascular function in hypercholesterolemia is preserved by chronic antioxidant supplementation.

Hypercholesterolemia impairs systemic vascular reactivity in response to endothelium-dependent vasodilators, which may be mediated partly through increased formation of lipid peroxides. However, it is unclear whether these pathophysiological mechanisms play a role in renal vascular impairment in experimental hypercholesterolemia. Hence, pigs were studied after a 3-mo normal (n = 7) or high cholesterol (HC) (n = 7) diet, HC diet supplemented daily with antioxidant vitamins E (100 IU/kg) and C (1000 mg; HC+vitamins, n = 5), or normal diet supplemented with vitamins (N+vitamins, n = 5). Renal blood flow was measured with electron-beam computed tomography before and during infusion of acetylcholine (Ach). Endothelial function, endothelial and inducible nitric oxide synthase (NOS), and nitrotyrosine immunoreactivity were studied in renal arteries ex vivo. Despite similar cholesterol levels, LDL oxidizability (lag time, malondialdehyde, and relative electrophoretic mobility) was increased in pigs that were fed the HC diet but was significantly decreased in pigs that were fed the HC+vitamins diet. Renal blood flow response to Ach was blunted in pigs that were fed the HC diet but was preserved in pigs that were fed the HC+vitamins diet. Maximal relaxation to Ach was attenuated in pigs that were fed the HC diet compared with those that were fed the normal diet (51.5 +/- 6.4% versus 97.0 +/- 2.9%; P < 0.01) but was preserved in pigs that were fed the HC+vitamins diet (103.1 +/- 3.0%; P = 0.39) and N+vitamins diet (87.7 +/- 3.0%; P = 0.1), as were relaxation responses to calcium ionophore A23187. Vascular smooth-muscle relaxation to diethylamine was enhanced in endothelium-denuded HC vessel but was restored in pigs that were on the HC+vitamins regimen. In HC, immuno-reactivity of endothelial NOS was decreased, that of inducible NOS was increased, and both were preserved in pigs that were fed the HC+vitamins and N+vitamins diets, whereas nitrotyrosine was not detected. The present study demonstrates that antioxidant intervention in experimental HC reduces LDL oxidizability and preserves renal vascular responses to endothelium-dependent vasodilators. Therefore, this beneficial effect potentially can protect the kidney from hypercholesterolemia-induced damage.

Animals↗

PubMedDate not supplied

c-Myc oncoprotein: a dual pathogenic role in neoplasia and cardiovascular diseases?

A growing body of evidence indicates that c-Myc can play a pivotal role both in neoplasia and cardiovascular diseases. Indeed, alterations of the basal machinery of the cell and perturbations of c-Myc-dependent signaling network are involved in the pathogenesis of certain cardiovascular disorders. Down-regulation of c-Myc induced by intervention with antioxidants or by antisense technology may protect the integrity of the arterial wall as well as neoplastic tissues. Further intervention studies are necessary to investigate the effects of tissue-specific block of c-Myc overexpression in the development of cardiovascular diseases.

Animals↗

PubMedDate not supplied

c-Myc oncoprotein: cell cycle-related events and new therapeutic challenges in cancer and cardiovascular diseases.

Advanced stages of both cancer and atherosclerosis are characterized by a local increase in tissue mass that may be hard to control. This increase in tissue mass can be attributed to oxidation-sensitive modification of cell cycle-related events, including cellular proliferation, differentiation, and apoptosis, which could be secondary to alteration in the activity of tumor suppressor gene and oncogene products. The oncogene c-Myc has classically been considered to be involved in carcinogenesis and has more recently been implicated in both endothelial dysfunction and atherogenesis as well. Consequently, inhibition of c-Myc-dependent signaling has become a novel therapeutic opportunity and challenge in atherosclerosis and other cardiovascular diseases. Antioxidant strategies, RNA synthesis inhibitors such as mithramycin, and gene therapeutic approaches with antisense oligonucleotides against c-Myc are some of the promising strategies. In general, the increased biologic understanding of the participation of cell cycle events and targeting these events may enable to attenuate or prevent some of the complications of vascular and neoplastic diseases.

Animals↗