IGF-1, Oxidative Stress and Cardiovascular Aging

心血管衰老是一个持续的、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)分泌不足和肝脏GH抵抗有关。生长激素分泌减少足以导致血清胰岛素样生长因子-1(IGF-1)下降，身体成分和代谢异常。有证据表明，IGF-1参与了心血管功能的调节。GH/IGF-1缺乏的患者表现出与老年患者相似的心功能障碍，主要表现为左室质量、射血分数和舒张期充盈减少。胰岛素样生长因子-1，生长激素在心脏生长、脂质代谢、细胞凋亡和氧化损伤中的主要介导者。氧化剂平衡在心脏保护中起着至关重要的作用，使心脏具有正常的收缩性能。令人信服的证据表明，随着年龄的增长，氧化损伤会加剧。我们的实验室已经表现出抵抗IGF-1诱导的高龄心脏收缩反应和IGF-1缺乏引起的心脏收缩功能受损的作用。我们的中心假设是，随着年龄的增长，IGF-1缺乏是氧化损伤增强和心功能障碍的最终原因。为了验证我们的假设，我们将应用最先进的细胞生物学、细胞生理学和转基因技术。在两种心肌IGF-1过度表达或循环IGF-1严重缺乏(肝脏IGF-1缺陷，LID)的转基因小鼠模型中，将评估静息或应激状态下心肌细胞的收缩功能、心脏兴奋收缩偶联、心肌收缩蛋白表达、氧化损伤/抗氧化防御和细胞凋亡。这些研究应该为IGF-1在心血管衰老发展过程中增强的氧化损伤和受损的心功能中的确切作用提供有价值的信息。我们的长期目标是确定心血管衰老过程中IGF-1缺乏、氧化损伤增加和心功能不全之间的因果联系，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.