Effect of Exercise Training on Lymphocyte Autophagy/Apoptosis Mediated by Beta-Adrenergic Receptor Signaling in Patients with Heart Failure

The high mortality in patients with heart failure (HF) is influenced by presence of multiple comorbidites. Immune dysfunction and consequent infection emerge as key causes of death in the HF patients. Leukocyte distribution is significantly altered in patient with chronic HF, which presents the decreases in the percentages of T helper and B lymphocytes in blood. Persistent sympathetic excitation and extreme oxidative stress caused by HF result in the deterioration of myocardial function and also may influence the regulation of immune system. In chronic HF, the deterioration of ventricular function is associated with alterations of cardiac -adrenergic receptor (-AR) signaling, which occurs by the uncoupling of remaining -ARs from increasing expression of G protein-coupling receptor kinases (GRKs). Down-regulation of GRK2 reduces myocardial apoptotic response to ischemia/reperfusion, possibly by activating AKt and increasing nitric oxidative production. Recent investigation have showed that myocardiac GRK2 expression/activity are mirrored by lymphocyte levels of this kinase, and its elevation in HF is related to the loss of -AR responsiveness and appears to increase with disease severity. Therefore, lymphocyte may provide a surrogate for monitoring cardiac GRK2. Physical training elicits beneficial effects on neurohumoral, inflammatory, redox, and immune regulations, leading to improvement in functional capacity and quality of life. These training-induced changes may effectively counteract the progression of deleterious compensatory mechanisms of HF and reduced the risk of noncardiac comorbidy as infection. Which exercise prescription yields maximal beneficial adaptation in immune function is controversial. Several lines of evidence suggest that aerobic interval training (AIT) is more effectively decreased sympathetic activity and plasma catecholamine level than traditional moderate continuous training (MCT) in patients with HF. Whether the -AR signaling mediated by AIT and/or MCT influences GRK-induced lymphocyte death signaling, as autophagy, apoptosis, or necrosis in patients with HF has not yet been investigated. Accordingly, we will conduct this three-year study that includes 1st year study: to clarify the relationship between HF severity and immune impairment by comparing the difference of -AR/GRK-mediated lymphocyte death pathways among HF patients with various functional capacities (New York Hear Association); 2nd year: the effects of acute interval and continuous exercise tests on -AR/GRK-mediated lymphocyte death signaling in patients with HF; and 3rd year study: the effects of chronic (3 months) AIT and MCT interventions on -AR/GRK-mediated lymphocyte death signaling in patients with HF. We expect that these results obtained from this study can aid in determining appropriate exercise intervention to improve aerobic fitness as well as simultaneously to enhance immune function and minimize the risk of deleterious comorbidites in patients with HF.

Project ID:PC10007-0393
External Project ID:NSC100-2314-B182-004-MY3