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

Not Applicable

Completed

Interventions: Other: Rhythmic Handgrip Exercise
Other: Chronic Exercise Training

Brief Summary: Aging is inevitable and is the primary risk factor for developing cardiovascular disease. The molecular mechanisms that drive vascular dysfunction in the context of aging are incompletely understood. The overall hypothesis is that the age-related decline in endothelial cell (EC) autophagy leads to arterial dysfunction. This study will determine whether physiological shear-stress affects autophagosome formation and nitrous oxide (NO) generation in ECs.

Detailed Description: 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.

Recruitment & Eligibility

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Arm && Interventions

Group	Intervention	Description
Healthy Older Adult Subjects	Rhythmic Handgrip Exercise	Healthy older adult subjects (\> 60 years) will be assessed for markers of EC autophagy, eNOS activation, and NO generation before and after Rhythmic Handgrip Exercise and after Chronic Exercise Training.
Healthy Adult Subjects	Rhythmic Handgrip Exercise	Healthy adult subjects (18 - 30 years) will be assessed for markers of EC autophagy, eNOS activation, and NO generation before and after Rhythmic Handgrip Exercise
Healthy Older Adult Subjects	Chronic Exercise Training	Healthy older adult subjects (\> 60 years) will be assessed for markers of EC autophagy, eNOS activation, and NO generation before and after Rhythmic Handgrip Exercise and after Chronic Exercise Training.

Primary Outcome Measures

Name	Time	Method
Change in biomarker beclin-1 after Rhythmic Handgrip Exercise	60 min
Change in biomarker Atg3 after Rhythmic Handgrip Exercise	60 min
Change in biomarker Atg5 after Rhythmic Handgrip Exercise	60 min
Change in biomarker Atg7 after Rhythmic Handgrip Exercise	60 min
Change in biomarker Lamp1 after Rhythmic Handgrip Exercise	60 min
Change in biomarker Lamp2 after Rhythmic Handgrip Exercise	60 min
Change in biomarker p62 after Rhythmic Handgrip Exercise	60 min
Change in biomarker beclin-1 after chronic exercise training	8 weeks
Change in biomarker Atg3 after chronic exercise training	8 weeks
Change in biomarker Atg5 after chronic exercise training	8 weeks
Change in biomarker Atg7 after chronic exercise training	8 weeks
Change in biomarker Lamp1 after chronic exercise training	8 weeks
Change in biomarker Lamp2 after chronic exercise training	8 weeks
Change in biomarker p62 after chronic exercise training	8 weeks

Secondary Outcome Measures

Name	Time	Method
Change in radial arterial diameter after chronic exercise training	8 weeks
Change in radial arterial flow rate after chronic exercise training	8 weeks
Change in radial arterial diameter after Rhythmic Handgrip Exercise	60 min
Change in radial arterial flow rate after Rhythmic Handgrip Exercise	60 min
Change in biomarker p-eNOSS1177 after Rhythmic Handgrip Exercise	60 min
Change in biomarker p-eNOSS1177 after chronic exercise training	8 weeks