Effects of Aging on Experimental Atherosclerosis in Nonhuman Primates
衰老对非人灵长类动物实验性动脉粥样硬化的影响
基本信息
- 批准号:9147248
- 负责人:
- 金额:$ 35.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AffectAgeAgingAnimal ModelAnimalsAnnexin A7Anti-Inflammatory AgentsAnti-inflammatoryApolipoprotein EApoptosisArterial Fatty StreakAtherogenic DietAtherosclerosisAttenuatedB-Cell ActivationB-LymphocytesBiochemical MarkersBiomedical EngineeringBlood VesselsBody WeightCCL2 geneCalciumCaliforniaCalmodulinCaloric RestrictionCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular systemCarotid ArteriesCell Culture TechniquesCellsCholesterolChronicClinicalCollaborationsCollectionComplement 1qComplement 2CysteineCytoskeletonDataDepositionDiagnosisDiastolic blood pressureDietDinoprostDiseaseDrosophila genusEndothelial CellsEnhancersErythrocytesEventExhibitsFamilyFatty acid glycerol estersFoam CellsGCLC geneGene ExpressionGene TargetingGenomicsGlucoseGlutathioneGlycineHarvestHeartInfiltrationInflammationInflammatoryIntegral Membrane ProteinInterleukin-1Interleukin-6LightLinkLipidsLongevityMacacaMacaca mulattaMeasuresMedialMessenger RNAMicroRNAsMicrofilamentsMitochondriaModelingMolecularMonkeysMorbidity - disease rateMyelin P0 ProteinMyocardialMyosin ATPaseNQO1 geneNuclearOxidation-ReductionOxidative StressPeptide Initiation FactorsPerformancePhenotypePhysiologic pulsePlasmaProductionPropertyProteinsProteomeProteomicsRattusResveratrolRisk FactorsRoleS100 ProteinsSerine ProteaseSerum Amyloid P-ComponentSignaling ProteinSmooth Muscle MyocytesSocietiesSucroseThickTissuesTriglyceridesTumor Necrosis Factor-alphaUniversitiesValidationVascular remodelingVentricular RemodelingVinculinVitronectinaflatoxin B1 aldehyde reductaseage effectage relatedagedapolipoprotein C-Iarterial remodelingascorbateatherogenesiscalcificationcytokinedesignfeedingflyfollow-uphemodynamicsimprovedisocitrate dehydrogenase (NADP+)macrophagemembermortalitynonhuman primatenovelnovel strategiesoverexpressionperiostinpreventsecretory proteinstress tolerancetranscription factortranscriptomics
项目摘要
Following collection of baseline data, 16 monkeys had been assigned to an atherogenic diet and 10 monkeys to a control diet. Baseline, cholesterol, triglycerides, and glucose were not different between the control and treated groups. At the second follow-up, cholesterol levels in the treated group were different from controls (p<0.0001). At the second follow-up, glucose was related with body weight in the controls but not in the treated group.
After sacrifice, we harvested arterial tissue. Histochemical observation and morphological analysis indicated that age increases intimal thickness and medial thickness along with atherosclerotic lesions in these domestic monkeys fed normal diets. Interestingly, age affects fat deposition within arterial walls in these domestic monkeys with high cholesterol diets. Importantly, we found that a high cholesterol diet increases adverse histopathologic events and plaque burden, which are closely associated with changes in cholesterol, glucose, diastolic blood pressure, pulse wave velocity. Further studies indicate that high cholesterol diet reprograms the aged arterial wall via further damage of endothelial integrity and macrophage infiltration, foam cell formation, and fat or calcium deposits, contributing to a vulnerable thickened intima for the accelerated occurrence of adverse histopathologic events, including plaque burden.
Comprehensive quantitative proteomic studies were designed to analyze proteomic changes of carotid arteries in the different conditions. We have found 8 proteins are less abundant and 12 proteins are more abundant in old animals. For example, the proteins which are less abundant are Protein S100-A6, Isocitrate dehydrogenase NADP, Myelin P0 protein, Myosin-7, Aldo-keto reductase family 1 member B10, Protein S100-A4, Calmodulin and SPATS2-like protein. The proteins which are more abundant include Programmed cell death protein 6, Periostin, Apolipoprotein E, Erythrocyte band 7 integral membrane protein, Translation initiation factor IF-2 Complement component C9, Lactadherin( MFG-E8), Apolipoprotein C-I Vitronectin, Annexin A7, Cysteine and glycine-rich protein 2, Serine protease HTRA1,Serum amyloid P-component and Complement C1q tumor necrosis factor-related protein.
micro RNA arrays of carotid arteries in monkeys with or without high cholesterol diets indicate that there are totally 91 modified miRs, via a continuous age analysis. 15 miRs significantly change with aging, 67 miRs are significantly different in abundance associated with high cholesterol diet treatment. Part of PCR validation results showed that miR-21, miR-34a, miR-155, miR-210, miR-199a, miR-199a-3p, miR-423-5p, let-7i are indeed modulated with age and/or high cholesterol diet treatment.
Furthermore, we found that carotid arteries of aged rhesus macaques exhibit significant oxidative stress (as indicated by the increased 8-iso-PGF2 and 4-HNE content and decreased glutathione and ascorbate levels) as compared with vessels of young macaques that is associated with activation of the redox-sensitive proinflammatory transcription factor, nuclear factor-kappaB. However, age-related oxidative stress does not activate Nrf2 and does not induce Nrf2 target genes (NQO1, GCLC, and HMOX1). In cultured vascular smooth muscle cells (VSMCs) derived from young monkeys, treatment with H(2)O(2) and high glucose significantly increases transcriptional activity of Nrf2 and upregulates the expression of Nrf2 target genes. In contrast, in cultured VSMCs derived from aged macaques, H(2)O(2)- and high glucose-induced Nrf2 activity and Nrf2-driven gene expression are blunted. High glucose-induced H(2)O(2) production was significantly increased in aged VSMCs compared with that in cells from young monkeys. Aged VSMCs cultured in the absence of systemic factors exhibited significantly increased secretion of interleukin-1, MCP-1, and tumor necrosis factor compared with young control cells. Secretion of interleukin-6 also tended to increase in aged VSMCs. This age-associated proinflammatory shift in the cellular secretory phenotype was associated with an increased mitochondrial O(2)(-) production and nuclear factor -light-chain-enhancer of activated B cells activation. Treatment of aged VSMCs with a physiologically relevant concentration of resveratrol exerted significant anti-inflammatory effects, reversing aging-induced alterations in the cellular cytokine secretion profile and inhibiting nuclear factor -light-chain-enhancer of activated B cells.
Interestingly, resveratrol treatment, mimicking calorie restriction, attenuated mitochondrial O(2)(-) production and upregulated the transcriptional activity of Nrf2 in aged monkey VSMCs. Resveratrol treatment also prevents the proinflammatory properties of the aged monkey VSMC secretome, an effect that likely contributes to the demonstrated vasoprotective action of resveratrol in animal models of aging. Importantly, resveratrol treatment prevents the proinflammatory properties of the aortic wall, an effect that likely contributes to the demonstrated vasoprotective action of resveratrol in nonhuman primates with a high fat diet, an early arterial aging model.
It is well known that central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of cardiovascular (CV) morbidity and mortality in Western society. An increase in central arterial wall stiffening, measured as an increase in aortic pulse wave velocity (PWV), is a major risk factor for clinical CV disease events. In rhesus monkeys, a 2 year diet high in fat and sucrose (HFS) increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening and increases PWV and inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall were driven by genomic and proteomic signatures of oxidative stress and inflammation. Very importantly, resveratrol prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV.
Importantly, in collaboration with Dr. Engler (Department of Bioengineering, University of California, San Diego), we found the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. Cardiac-restricted vinculin overexpression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility and hemodynamic stress tolerance in healthy and myosin-deficient fly hearts. Moreover, cardiac-specific vinculin overexpression markedly increased median life span in flies. These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity in flies, rats, and monkeys.
在收集基线数据后,16只猴子被分配到致动脉粥样硬化饮食组,10只猴子被分配到对照饮食组。基线、胆固醇、甘油三酯和葡萄糖在对照组和治疗组之间没有差异。在第二次随访中,治疗组的胆固醇水平与对照组不同(p<0.0001)。在第二次随访中,对照组的血糖与体重相关,但治疗组没有。
项目成果
期刊论文数量(0)
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Edward Lakatta其他文献
Edward Lakatta的其他文献
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{{ truncateString('Edward Lakatta', 18)}}的其他基金
Decreased pacemaker activity in aged sinoatrial node
老年窦房结起搏器活动减少
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8335801 - 财政年份:
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$ 35.73万 - 项目类别:
Soluble Receptor for Advanced Glycation End Products for Therapeutic Application
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8552494 - 财政年份:
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8736511 - 财政年份:
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