IGF-1, Oxidative Stress and Cardiovascular Aging

University Of Wyoming, Laramie WY

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Abstract

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.