Aging, Insulin Resistance, and Dilated Cardiomyopathy

衰老、胰岛素抵抗和扩张型心肌病

• 批准号: 7002279
• 负责人: Richard P Shannon
• 金额: $ 32.96万
• 依托单位: ALLEGHENY-SINGER RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002279
• 关键词: age difference; aging; animal mortality; animal old age; biological signal transduction; dogs; free fatty acids; gait; glucose clamp technique; glucose transport; heart failure; heart ventricle; hemodynamics; immunocytochemistry; incretin hormone; insulin sensitivity /resistance; myocardium; myocardium disorder; oxidation; peroxisome proliferator activated receptor; phosphomonoesterases; recombinant proteins; statistics /biometry; terminal nick end labeling; western blottings

DESCRIPTION (provided by applicant): Congestive heart failure is a leading cause of morbidity and mortality in the elderly, although the mechanisms to explain the enhanced proclivity are poorly understood. It remains debatable as to whether the age-associated propensity to cardiovascular dysfunction is attributable to aging per se or the accumulation of cardiovascular risk factors that accrue over time. In particular, aging has been closely associated with the development of increased visceral adiposity that has been implicated in the pathogenesis of age associated insulin resistance. Whether age associated insulin resistance contributes to the progression of cardiac dysfunction following myocardial injury has not been explored systematically. The altered cellular actions of insulin that underlie physiological insulin resistance may have significant consequences to the failing heart. The injured myocardium develops an evolving dependence on glucose as its preferred metabolic substrate. The preference is dependent upon the efficiencies of oxidation of glucose in the generation of high-energy phosphates. This preference becomes a requirement as the ability to oxidized fat acids is limited through a series of molecular switches in key regulatory components of fatty acid transport and oxidation. We have determined that advanced, decompensated stages of dilated cardiomyopathy are associated with the development of myocardial insulin resistance, which limits myocardial glucose uptake and oxidation. These physiological features are associated with cellular insulin signaling abnormalities in the myocardium that are distinct from those observed in skeletal muscle and adipose tissue in other insulin resistant states. Together, aging and heart failure share the common pathophysiological features of insulin resistance. Whether the effects are additive or synergistic in explaining the increased incidence and severity of heart failure in the elderly remains to be determined. We will determine if aging is associated with accelerated progression of heart failure in conscious dogs with pacing induced dilated cardiomyopathy. We will define the physiological and cellular effects of insulin resistance in the senescent myocardium during the evolution of dilated cardiomyopathy. Finally, we will determine if overcoming myocardial insulin resistance in the aging and failing heart will prevent the progression of dilated cardiomyopathy.

描述（由申请人提供）：充血性心力衰竭是老年人发病和死亡的主要原因，尽管对解释增强倾向的机制知之甚少。年龄相关的心血管功能障碍倾向是由于年龄本身还是随着时间的推移心血管危险因素的积累，这一点仍然存在争议。特别是，衰老与内脏肥胖增加的发展密切相关，内脏肥胖增加与年龄相关的胰岛素抵抗的发病机制有关。年龄相关的胰岛素抵抗是否有助于心肌损伤后心功能不全的进展尚未系统地探讨。胰岛素细胞作用的改变是生理性胰岛素抵抗的基础，可能对衰竭的心脏产生重大影响。受损的心肌逐渐依赖葡萄糖作为其首选的代谢底物。该偏好取决于在产生高能磷酸盐中葡萄糖氧化的效率。由于氧化脂肪酸的能力通过脂肪酸转运和氧化的关键调节组分中的一系列分子开关而受到限制，因此这种偏好成为一种要求。我们已经确定扩张型心肌病的晚期失代偿期与心肌胰岛素抵抗的发展有关，胰岛素抵抗限制了心肌葡萄糖的摄取和氧化。这些生理特征与心肌中的细胞胰岛素信号传导异常相关，其不同于在其他胰岛素抵抗状态下在骨骼肌和脂肪组织中观察到的那些。总之，衰老和心力衰竭具有胰岛素抵抗的共同病理生理学特征。在解释老年人心力衰竭的发病率和严重程度增加时，这些效应是累加的还是协同的仍有待确定。我们将确定年龄是否与起搏诱导扩张型心肌病清醒犬心力衰竭加速进展有关。我们将明确扩张型心肌病发展过程中衰老心肌中胰岛素抵抗的生理和细胞效应。最后，我们将确定在衰老和衰竭的心脏中克服心肌胰岛素抵抗是否会阻止扩张型心肌病的进展。