IGF-1, Oxidative Stress and Cardiovascular Aging

心血管老化是一个持续和不可逆转的过程，是老年人最常见的死亡原因。高龄与生长激素（GH）产生不足和肝脏GH抵抗有关。生长激素分泌减少足以引起血清胰岛素样生长因子-1 （IGF-1）下降，机体成分和代谢异常。有证据表明，IGF-1参与心血管功能的调节。GH/IGF-1缺乏的患者表现出与衰老患者相似的心功能障碍，主要表现为左心室体积、射血分数和舒张充盈减少。IGF-1，生长激素在心脏生长、脂质谱、细胞凋亡和氧化损伤中的主要介质。氧化平衡在心脏保护中起着至关重要的作用，允许正常的心脏收缩性能。令人信服的证据表明，氧化损伤随着年龄的增长而增强。我们的实验室已经证明，在IGF-1缺乏的情况下，老年人对IGF-1诱导的心脏收缩反应有抵抗性，心脏收缩功能受损。我们的中心假设是IGF-1缺乏与老年是氧化损伤和心室功能障碍增强的最终原因。为了验证我们的假设，最先进的细胞生物学，细胞生理学和转基因技术将被应用。在两种心肌IGF-1过表达或循环IGF-1严重缺乏（肝脏IGF-1缺陷，LID）的转基因小鼠模型中，我们将评估静止或应激状态下心室肌细胞的收缩功能、心脏兴奋-收缩耦合、心脏收缩蛋白表达、氧化损伤/抗氧化防御和细胞凋亡。这些研究将为IGF-1在心血管衰老过程中氧化损伤增强和心室功能受损中的确切作用提供有价值的信息。我们的长期目标是在心血管衰老过程中建立IGF-1缺乏、氧化损伤增强和心室功能障碍之间的因果关系，以便优化激素或抗氧化治疗。

Cardiovascular aging is a continuous and irreversible process that accounts for the most common cause of death in the elderly. Advanced age is associated with insufficient production of growth hormone (GH) and hepatic GH resistance. The reduced GH secretion is sufficient to cause a fall in the serum insulin-like growth factor-1 (IGF-1), abnormal body composition and metabolism. Evidence has indicated that IGF-1 are involved in the regulation of cardiovascular function. Patients with GH/IGF-1 deficiency displayed cardiac dysfunctions similar to those seen in aging, manifested primarily as reduced left ventricular mass, ejection fraction, and diastolic filling. IGF-1, the main mediator of GH in cardiac growth lipid profile, apoptosis and oxidative damage. Oxidant balance plays a crucial role in cardiac protection, allowing normal cardiac contractile performance. Compelling evidence suggested enhanced oxidative damage with aging. Our lab has shown resistance to IGF-1 induced cardiac contractile response with advanced age and impaired cardiac contractile function under IGF-1 deficiency. Our central hypothesis is that IGF-1 deficiency with advanced age is the ultimate cause of enhanced oxidative damage and ventricular dysfunction. To test our hypothesis, state-of-the-art cell biology, cell physiology and transgenic techniques will be applied. Contractile function of ventricular myocyte under rest or stress, cardiac excitation-contraction coupling, cardiac contractile protein expression, oxidative damage/antioxidant defense and apoptosis will be evaluated in two transgenic mouse models with either cardiac IGF-1 over-expression or severe deficiency in circulating IGF-1 (liver IGF-1 deficient, LID). These studies should provide valuable information for the precise role of IGF-1 in the enhanced oxidative damage and impaired ventricular function en route to the development of cardiovascular aging. Our long-term goal is to establish the causal link among IGF-1 deficiency, enhanced oxidative damage and ventricular dysfunction in the progression of cardiovascular aging so that hormonal or antioxidant therapy can be optimized.