Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0729233 (Thoracic)
 6,478 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Given the beneficial effects of HMG-CoA reductase and ACAT inhibitors on hypercholesterolemia and atherosclerosis, we hypothesized that coadministration would improve the hypolipidemic response and not only limit lesion development but also alter the cellular composition of atherosclerotic lesions so as to induce a stable atherosclerotic lesion morphology. Plasma total cholesterol exposure was reduced 29 and 39% with atorvastatin (2.5 mg/kg) and CI-976 (5 mg/kg), respectively, and 60% upon coadministration due primarily to reductions in VLDL-cholesterol. Modest changes in liver cholesterol ester (CE) content were observed with atorvastatin or CI-976; however, a striking 48% reduction was noted upon coadministration. Liver HMG-CoA reductase mRNA levels were reduced 73% by cholesterol feeding and drug treatment did not prevent the reduction; however, atorvastatin alone and upon coadministration blunted the decrease in LDL receptor mRNA levels. The CE content of the iliac-femoral was unaffected by atorvastatin but was reduced 35% by CI-976 and 53% upon coadministration. Thoracic aortic CE content was reduced 38% by atorvastatin, 48% by CI-976 and 80% upon coadministration. Iliac-femoral lesion and macrophage area were reduced 48 and 67% by atorvastatin, respectively, and 68 and 81% by CI-976 but upon coadministration only an 85% reduction in macrophage area was noted. Aortic arch cross-sectional lesion and macrophage area were unaffected by atorvastatin, decreased 72-80% by CI-976 and reduced 87-92% upon coadministration. We conclude that inhibition of HMG-CoA reductase and ACAT acts synergistically to lower plasma total and lipoprotein cholesterol levels and to limit the development of atherosclerotic lesions in the cholesterol-fed rabbit by presumably regulating cholesterol trafficking pathways within liver and vascular cells.
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PMID:HMG-CoA reductase and ACAT inhibitors act synergistically to lower plasma cholesterol and limit atherosclerotic lesion development in the cholesterol-fed rabbit. 969 88

Background: Endothelial dysfunction plays a pivotal role in the initiation of atherosclerosis. Vascular insulin resistance might contribute to a reduction in endothelial nitric oxide (NO) production, leading to impaired endothelium-dependent relaxation in cardiometabolic diseases. Because perivascular adipose tissue (PVAT) controls endothelial function and NO bioavailability, we hypothesized a role for this fat deposit in the vascular complications associated with the initial stages of atherosclerosis. Therefore, we investigated the potential involvement of PVAT in the early endothelial dysfunction in hypercholesterolemic LDL receptor knockout mice (LDLr-KO). Methods: Thoracic aortas with and without PVAT were isolated from 4-month-old C57BL/6J (WT) and LDLr-KO mice. The contribution of PVAT to relaxation responses to acetylcholine, insulin, and sodium nitroprusside was investigated. Western blotting was used to examine endothelial NO synthase (eNOS) and adiponectin expression, as well the insulin signaling pathway in aortic PVAT. Results: PVAT-free aortas of LDLr-KO mice exhibited impaired acetylcholine- and insulin-induced relaxation compared with those of WT mice. Both vasodilatory responses were restored by the presence of PVAT in LDLr-KO mice, associated with enhanced acetylcholine-induced NO levels. PVAT did not change vasodilatory responses to acetylcholine and insulin in WT mice, while vascular relaxation evoked by the NO donor sodium nitroprusside was not modified by either genotype or PVAT. The expression of insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), AKT, ERK1/2, phosphorylation of AKT (Ser473) and ERK1/2 (Thr202/Tyr204), and adiponectin was similar in the PVAT of WT and LDLr-KO mice, suggesting no changes in PVAT insulin signaling. However, eNOS expression was enhanced in the PVAT of LDLr-KO mice, while eNOS expression was less abundant in PVAT-free aortas. Conclusion: These results suggest that elevated eNOS-derived NO production in aortic PVAT might be a compensatory mechanism for the endothelial dysfunction and impaired vasodilator action of insulin in hypercholesterolemic LDLr-deficient mice. This protective effect may limit the progression of atherosclerosis in genetic hypercholesterolemia in the absence of an atherogenic diet.
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PMID:Protective Role of Perivascular Adipose Tissue in Endothelial Dysfunction and Insulin-Induced Vasodilatation of Hypercholesterolemic LDL Receptor-Deficient Mice. 2961 24