Effect of Age on Exercise-Induced Cardioprotection

Starnes, Joseph

Abstract

This proposal is in response to research topic #2: Cardiovascular and Cerebral aging as described in PAR-02-049. Long-term exercise participation reduces deaths from heart attacks and lowers the risk of cardiovascular disease, the leading cause of death and health care expense in the US. Many investigations into the mechanisms for how exercise protects the heart have focused on its intrinsic ability to recover from a bout of ischemia, which is both clinically relevant and a powerful tool to probe basic myocardial protective systems. There is now overwhelming evidence that exercise results in intrinsic cardioprotection. Surprisingly, all of this evidence comes from studies using young animals. It may not be appropriate to extrapolate this data to the middle aged and elderly, who experience almost all of the cardiac complications. For example, several studies conclude that increased expression of inducible 70 kDalton heat shock protein (HSP70) is necessary for exercise-induced cardioprotection; however, this protein is not increased in the hearts of aged animals after exercise. Our overall hypothesis is that appropriate exercise will provide cardioprotection in mature adult and aged animals, but that the protective phenotype will vary by age. The first Specific Aim is to determine whether 10-12 weeks of exercise on a motorized treadmill will result in preconditioning against myocardial and endothelial ischemia-reperfusion injury in young, mature adult and aged rats. Isolated perfused working hearts of sedentary and exercise-trained male Fischer 344 rats aged 6, 15, and 24 months will be evaluated for hemodynamic and vascular function, cytosolic enzyme leakage, nitric oxide release, oxidative stress, and area of no-reflow before and after ischemia. The second Specific Aim is to gain insight into how aging affects the cellular adaptations that mediate exercise-induced cardioprotection. Correlations will be determined between Aim 1 results and the amount and activity (as appropriate) of several relevant proteins in the heart prior to the ischemic stress. These include: heat shock proteins (HSP70 and HSP 25/27), nitric oxide synthase isozymes, antioxidant enzymes, and mitogen activated protein kinases. The cellular redox state as indicated by GSH/GSSG will also be measured. The results of this Aim will provide key direction for the effective design of further comprehensive studies using inhibitors and/or activators of specific proteins or signaling pathways.