Autophagy Maintains Vascular Function Through a Novel Glycolysis-linked Pathway Regulating eNOS

It is hypothesized that genetic autophagy suppression prevents shear-stress induced purinergic signaling to endothelial nitrous oxide synthase (eNOS) and this pathway will be evaluated in primary arterial ECs obtained from older adult (> 60 years) and adult (18-30 years) subjects before and following rhythmic handgrip exercise that elevates brachial artery shear-rate similarly in both groups. ECs will be used to quantify markers of EC autophagy, eNOS activation, and NO generation. The study will also determine whether exercise-training attenuates the aging-associated decline in EC autophagy, and whether intact autophagy is required for training-induced vascular improvements. To evaluate this potential, it will be determined whether one-limb rhythmic handgrip exercise training by older adult (> 60 y) human subjects is sufficient to elevate basal and shear-induced EC autophagy initiation, eNOS activation, and NO generation vs. the contralateral sedentary limb. Results from this work have tremendous potential to reveal a new therapeutic target and approach for restoring / maintaining vascular function in the aging population.

Inclusion criteria

• Candidates must be between 18 and 90 y of age
• Candidates must be free of overt disease as assessed by a) medical history; b) standard blood chemistries (chem. 7 panel), c) ECG at rest; d) limb vascular examination (ankle-brachial BP index > 0.9); e) resting BP < 140/90 mmHg; and f) skinfold % body fat assessment.
• Subjects will have a body mass index (BMI) between 19 and 30 and have plasma glucose concentrations < 7.0 mmol/L under fasting conditions and < 11.1 mmol/L at 120 minutes of an oral glucose tolerance test (OGTT)

Exclusion criteria

• Candidates <18 or >90 y of age
• Candidates demonstrating abnormal ECG, ankle-brachial BP index <0.9, resting BP > 140/90
• Candidates demonstrating a BMI <19 or > 30
• Candidates demonstrating plasma glucose concentrations > 7.0 mmol/L under fasting conditions and > 11.1 mmol/L at 120 minutes of an oral glucose tolerance test (OGTT)
• Candidates demonstrating dyslipidemia (plasma total cholesterol > 240 mg/dl with LDL-cholesterol > 160 mg/dl)
• Candidates reporting a history of myocardial infarction, unstable cardiac ischemia, recent cardiac catheterization, carotid artery disease, transient ischemic attack
• Women taking hormone replacement therapy (HRT) currently or in the preceding year will be excluded from the proposed studies due to the direct vascular effects of HRT.