RESUMEN

Ansamycins are hypolipidemic compounds which, when administered to various animal species, dramatically lower high density lipoprotein (HDL) cholesterol levels, in addition to reducing the levels of other lipoprotein classes. The current study tested one of these ansamycins (CGP 43371) for its hypolipidemic and anti-atherosclerotic activity in cholesterol-fed rabbits. Rabbits were fed a 0.25% cholesterol-enriched diet with or without admixed CGP 43371, equivalent to 30 mg/kg per day for 16 weeks. Compared with control rabbits, CGP 43371 treatment lowered total cholesterol levels (46%, P<0.05) and lipoprotein cholesterol levels (HDL, 58%; VLDL, 49% [both P<0.05]; LDL, 28% [not significant]). Despite the dramatic lowering of HDL cholesterol levels, aortic atherosclerosis, assessed by grossly visible sudanophilia, was significantly inhibited versus controls (total aorta=38%; aortic arch=32%; thoracic aorta=60%). Of particular note in CGP 43371-treated rabbits was a striking splenomegaly, which correlated with the presence of massive accumulations of macrophage foam cells in the splenic red pulp. We speculate that CGP 43371 inhibits the development of atheroselerotic lesions in rabbits by both a hypolipidemic mechanism, and by a mechanism(s) in which macrophage foam cells accumulate in the spleen.

Asunto(s)

Anticolesterolemiantes/farmacología , Arteriosclerosis/prevención & control , Células Espumosas/patología , Hígado/patología , Peritoneo/patología , Rifampin/análogos & derivados , Rifampin/farmacología , Bazo/patología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/patología , Arteriosclerosis/sangre , Arteriosclerosis/inducido químicamente , Arteriosclerosis/patología , División Celular/efectos de los fármacos , Colesterol/sangre , Colesterol en la Dieta/toxicidad , Células Espumosas/efectos de los fármacos , Lipoproteínas/sangre , Hígado/efectos de los fármacos , Masculino , Peritoneo/efectos de los fármacos , Conejos , Ratas , Ratas Sprague-Dawley , Bazo/efectos de los fármacos

Asunto(s)

Apolipoproteínas E/deficiencia , Arteriosclerosis/enzimología , Colagenasas/genética , Regulación Enzimológica de la Expresión Génica , Metaloproteinasa 3 de la Matriz/genética , Metaloendopeptidasas/genética , Transcripción Genética , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/fisiología , Arteriosclerosis/genética , Dieta Aterogénica , Predisposición Genética a la Enfermedad , Metaloproteinasa 12 de la Matriz , Metaloproteinasa 13 de la Matriz , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética

RESUMEN

The broad-spectrum MMP inhibitor CGS 27023A was tested to determine its potential as a therapy for atherosclerosis, aneurysm, and restenosis. LDL receptor-deficient (LDLr -/-) mice fed a high-fat, cholic acid-enriched diet for 16 weeks developed advanced aortic atherosclerosis with destruction of elastic lamina and ectasia in the media underlying complex plaques. Lesion formation correlated with a 4.6- to 21.7-fold increase in MMP-3, -12, and -13 expression. Treatment with CGS 27023A (p.o., b.i.d. at 50 mg/kg) had no effect on the extent of aortic atherosclerosis (36 +/- 4% versus 30 +/- 2% in controls), but both aortic medial elastin destruction and ectasia grade were significantly reduced (38% and 36%, respectively, p < 0.05). In the rat ballooned-carotid-artery model, CGS 27023A (12.5 mg/kg/day via osmotic minipump) reduced smooth muscle cell migration at 4 days by 83% (p < 0.001). Intimal lesions were reduced by 85% at 7 days (p < 0.001), but intimal smooth muscle proliferation was unaffected, and inhibitory efficacy was lost with time. At 12 days, intimal lesion reduction was less potent (52%, p < 0.01). At 3 and 6 weeks, reductions of 11% and 4%, respectively, were not significant. This demonstrates that it is essential to include late time points when the ballooned-carotid-artery model is employed to ensure that lesion size does not "catch up" when a compound solely inhibits smooth muscle cell migration. In summary, MMP inhibitor therapy delayed but did not prevent intimal lesions, thereby demonstrating little promise to prevent restenosis. In contrast, MMP inhibitor therapy may prove useful to retard progression of aneurysm.

Asunto(s)

Arteriosclerosis/fisiopatología , Arterias Carótidas/fisiopatología , Colagenasas/genética , Ácidos Hidroxámicos , Metaloproteinasa 3 de la Matriz/genética , Metaloendopeptidasas/antagonistas & inhibidores , Metaloendopeptidasas/genética , Inhibidores de Proteasas/farmacología , Pirazinas , Receptores de LDL/fisiología , Animales , Aorta Abdominal/patología , Aorta Abdominal/fisiopatología , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/fisiopatología , Aneurisma de la Aorta Abdominal/prevención & control , Arteriosclerosis/enzimología , Arteriosclerosis/patología , Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas , Cateterismo , Movimiento Celular , Elastina/metabolismo , Masculino , Metaloproteinasa 12 de la Matriz , Metaloproteinasa 13 de la Matriz , Ratones , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Receptores de LDL/deficiencia , Receptores de LDL/genética , Recurrencia , Sulfonamidas , Transcripción Genética

RESUMEN

We reported earlier that a complex familial hypercholesterolemia (c-FHC) phenotype characterized by elevated levels of total plasma cholesterol (TC) and apoB and reduced levels of HDL cholesterol (HDL-C) and apoA-I is associated with the development of spontaneous atherosclerotic lesions in swine. In this study, we investigated concentrations of plasma lipids and apolipoproteins B, C-III, and E in six parental animals of two cholesterol concentration phenotypes and their 32 offspring, which segregated into high, intermediate, and normal cholesterol phenotypes. Subsequently, we compared the extent of atherosclerotic lesion development in coronary arteries to the concentrations of plasma lipids and apolipoproteins in the parents and two offspring per family. Mean concentrations for the high (n = 23), intermediate (n = 13), and normal (n = 2) cholesterol level phenotypes at 4 months of age were TC, 316 +/- 62.2, 159 +/- 17.1, and 105 +/- 12 mg/dL; LDL cholesterol, 275 +/- 63.1, 113 +/- 16.4, and 67 +/- 18.4 mg/dL; HDL-C, 35 +/- 6.1, 41 +/- 5.7, and 33 +/- 6.4 mg/dL; triglycerides, 48 +/- 10.8, 39 +/- 8.0, and 29 +/- 5.7 mg/dL; apoB, 152 +/- 32.5, 80 +/- 7.2, and 48 +/- 5.7 mg/dL; apoC-III, 10 +/- 4.2, 8 +/- 1.7, and 3 +/- 0.1 mg/dL; and apoE, 17 +/- 3.4, 7 +/- 1.7, and 5 +/- 0.7 mg/dL, respectively. Histological analysis of the major coronary arteries from members of the three families showed considerable variation in the severity of lesions, ranging from foci of adaptive intimal thickening consisting of two to six layers of smooth muscle cells to advanced lesions containing necrotic cores, cholesterol clefts, calcification, and hemorrhage (type V). The most extensive lesions occurred only in animals of the high cholesterol phenotype (ie, c-FHC), in which the concentration of TC and apoB progressively increased after 4 months of age, apoC-III, apoE, and triglycerides increased or remained elevated, and HDL-C decreased, except for one animal. Data presented here show that the plasma cholesterol phenotypes in FHC animals are associated with levels of apolipoproteins B, C-III, and E and indicate that the increases in the studied parameters after 4 months of age correlate with the progression of coronary artery disease.

Asunto(s)

Apolipoproteínas/sangre , Enfermedad Coronaria/etiología , Enfermedad Coronaria/patología , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/patología , Lípidos/sangre , Animales , Apolipoproteína C-III , Apolipoproteínas B/sangre , Apolipoproteínas C/sangre , Apolipoproteínas E/sangre , Arterias/patología , Vasos Coronarios/patología , Femenino , Masculino , Concentración Osmolar , Porcinos

RESUMEN

The development of advanced coronary atherosclerosis was studied in the FHC swine. This model exhibits spontaneous elevations in plasma cholesterol, LDL, and apo B while fed a low-cholesterol, low-fat diet. Hypercholesterolemic animals bearing the apo B genotypes Lpb2/3, 3/3, 3/5, 5/5 and 3/8 developed stenotic coronary lesions containing necrotic cores, fibrous caps, calcification, neovascularization, hemorrhage, and fissuring. Myocardial infarction and myocardial ischemia were also observed. The complicated atherosclerotic plaques observed in this swine model closely resemble advanced coronary artery disease (CAD) found in humans. While coronary atherosclerosis was not observed in the absence of hypercholesterolemia, neither the apo B genotype nor the level of hypercholesterolemia was found to predict the extent of lesion formation. Similar to the case in humans, the familial dyslipidemia associated with the development of CAD in the FHC swine appears to be polygenic.

Asunto(s)

Apolipoproteínas B/genética , Arteriosclerosis/genética , Enfermedad Coronaria/genética , Hiperlipoproteinemia Tipo II/veterinaria , Factores de Edad , Alelos , Animales , Apolipoproteínas B/inmunología , Arteriosclerosis/patología , Enfermedad Coronaria/patología , Femenino , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/patología , Masculino , Porcinos , Enfermedades de los Porcinos/genética