Cardiac protective mechanisms of melanocortin system activation
黑皮质素系统激活的心脏保护机制
基本信息
- 批准号:10585732
- 负责人:
- 金额:$ 58.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-09 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AgonistAmericanAnimal ModelAnimalsAnterior Descending Coronary ArteryAortaAreaBackBiogenesisBloodBlood - brain barrier anatomyBrainBrain StemBypassCardiacCardiac MyocytesCardiac OutputCardiovascular DiseasesCardiovascular systemCell NucleusCentral Nervous SystemCerebral VentriclesChronicCongestive Heart FailureDataDiameterDisease ProgressionDoseEFRACEchocardiographyEnergy MetabolismGeneticGenetic EngineeringGlucoseHealthcareHeartHeart failureHumanHypothalamic structureImaging TechniquesImaging technologyIn VitroInfusion proceduresKnock-outLateralLeftLeft atrial structureLeft ventricular structureLeptinLeptin resistanceLigationMeasurementMeasuresMediatingMelanocortin 4 ReceptorMetabolicMetabolic stressMitochondriaMolecularMorbidity - disease rateMorphologyMusMuscle functionMuscle strainMyocardial InfarctionMyocardial dysfunctionMyocardiumObesityOutcome StudyPathway interactionsPatientsPeripheralPreparationProductionProtocols documentationRattusReceptor ActivationResistanceResolutionRiskRisk FactorsSirtuinsSystemTestingThinnessUnited Statesblood-brain barrier crossingcardioprotectioncare burdencholinergic neurondorsal motor nucleuseffective therapyexercise capacityfatty acid oxidationheart functionheart preservationimprovedin vivoinnovationmelanotan-IImortalitynovelnovel therapeutic interventionobese patientsobesity geneticsoxidationparaventricular nucleuspreventprotective effectsuccesstherapeutically effectiveultrasound
项目摘要
PROJECT SUMMARY/ABSTRACT
Over 1.5 million Americans suffer from myocardial infarction (MI) each year, and about 25% of these patients
develop severe cardiac dysfunction including congestive heart failure (HF), which has a high 5-year mortality
rate of ~50%. Current therapies following MI have limited success in attenuating cardiac dysfunction and slowing
HF progression. Thus, there is a critical need for novel, more effective therapies that protect the heart, improve
its function, and slow/halt progression of cardiac dysfunction. We recently demonstrated that activation of the
brain leptin-melanocortin system pathway greatly improves cardiomyocyte energy metabolism and contractility,
preserves cardiac function, and prevents progression of HF following MI induced by ligation of the left anterior
descending coronary artery. We observed that intracerebroventricular (ICV) infusion of leptin for 4 weeks, at a
low dose that did not alter blood leptin concentration, restored ejection fraction, cardiac output, left ventricle (LV)
muscle strain and left atrium/aorta diameter ratio almost all the way back to normal baseline values, and
preliminary data suggest that other measures of cardiac function such as +dP/dtmax and exercise capacity were
also markedly improved. We also observed that these cardiac protective effects are absent in melanocortin 4
receptor (MC4R) deficient rats and that activation of brain MC4R using synthetic agonists infused into the
cerebral ventricles protected the heart against progressive cardiac dysfunction after MI in a similar fashion
compared to leptin treatment. Our preliminary data also indicate that activation of the CNS leptin-MC4R pathway
increases sirtuin-3 (SIRT3) expression, mitochondrial biogenesis and substrate oxidation (i.e., glucose and fatty
acid oxidation), and improves cardiomyocyte contractility in non-infarcted regions of the LV, including areas at
risk but still viable. The central hypothesis of this proposal is that activation of the brain melanocortin system
improves cardiac function and prevents progression of HF after MI, increases myocardium
mitochondrial biogenesis and SIRT3 levels, enhances substrate oxidation, and improves energy
production and cardiomyocyte contractility in healthy portions of the heart. We also propose that these
beneficial effects of the melanocortin system on the heart require MC4R activation in PVN and/or
DMV/NTS/IML, and that MC4R agonists that cross the blood-brain barrier (e.g. setmelanotide) and can
be administered systemically will be effective to provide cardioprotective even in the setting of obesity.
We will use state-of-the-art chronic in vivo protocols with high-resolution ultrasound techniques for imaging
cardiac function (including 4D-strain echocardiographic imaging technology) in genetically engineered animal
models combined with ex vivo and in vitro preparations for detailed measurements of cardiac muscle function,
morphology, energy metabolism and contractility to test our hypotheses. The outcomes from this study could
lead to novel and more effective therapeutic approaches for MI and HF, and will provide a new target for MC4R
agonists which are currently being used to treat rare forms of genetic obesity in humans.
项目总结/文摘
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Alexandre Alves da Silva其他文献
High-fat diets are detrimental of the lipid profile, glucose metabolism and body composition of Wistar rats: the role of fatty acid type and consumption duration
高脂肪饮食对 Wistar 大鼠的血脂、糖代谢和身体成分有害:脂肪酸类型和食用持续时间的作用
- DOI:
10.1108/nfs-07-2020-0282 - 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Arthur Rocha;Juliana Dara Silva;Thais Angélica Morais;A. M. R. Ferreira;Viviane Cristina Costa;Amanda Escobar Teixeira;M. R. Lessa;Alexandre Alves da Silva;N. V. Dessimoni;T. R. Riul - 通讯作者:
T. R. Riul
Alexandre Alves da Silva的其他文献
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