Clinical trial NCT04200560: Autophagy Maintains Vascular Function Through a Novel Glycolysis-linked Pathway Regulating eNOS
Official title: Autophagy Maintains Vascular Function Through a Novel Glycolysis-linked Pathway Regulating eNOS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Vascular Diseases
Keywords: Aging
Endothelial Cell Autophagy
Lead sponsor: University of Utah
Sponsor class: OTHER
First posted: 2019-12-16
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in biomarker beclin-1 after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in biomarker Atg3 after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in biomarker Atg5 after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in biomarker Atg7 after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in biomarker Lamp1 after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in biomarker Lamp2 after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in biomarker p62 after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in biomarker beclin-1 after chronic exercise training
timeFrame: 8 weeks
measure: Change in biomarker Atg3 after chronic exercise training
timeFrame: 8 weeks
measure: Change in biomarker Atg5 after chronic exercise training
timeFrame: 8 weeks
measure: Change in biomarker Atg7 after chronic exercise training
timeFrame: 8 weeks
measure: Change in biomarker Lamp1 after chronic exercise training
timeFrame: 8 weeks
measure: Change in biomarker Lamp2 after chronic exercise training
timeFrame: 8 weeks
measure: Change in biomarker p62 after chronic exercise training
timeFrame: 8 weeks
Secondary outcomes:
measure: Change in radial arterial diameter after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in radial arterial flow rate after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in biomarker p-eNOSS1177 after Rhythmic Handgrip Exercise
timeFrame: 60 min
measure: Change in radial arterial diameter after chronic exercise training
timeFrame: 8 weeks
measure: Change in radial arterial flow rate after chronic exercise training
timeFrame: 8 weeks
measure: Change in biomarker p-eNOSS1177 after chronic exercise training
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: VA Medical Center
state: Utah
Study officials:
References: