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

Primary Purpose

Vascular Diseases

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Rhythmic Handgrip Exercise

Chronic Exercise Training

About this trial

This is an interventional basic science trial for Vascular Diseases focused on measuring Aging, Endothelial Cell Autophagy

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

VA Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Healthy Adult Subjects

Healthy Older Adult Subjects

Arm Description

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 (> 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.

Outcomes

Primary Outcome Measures

Change in biomarker beclin-1 after Rhythmic Handgrip Exercise

Change in biomarker Atg3 after Rhythmic Handgrip Exercise

Change in biomarker Atg5 after Rhythmic Handgrip Exercise

Change in biomarker Atg7 after Rhythmic Handgrip Exercise

Change in biomarker Lamp1 after Rhythmic Handgrip Exercise

Change in biomarker Lamp2 after Rhythmic Handgrip Exercise

Change in biomarker p62 after Rhythmic Handgrip Exercise

Change in biomarker beclin-1 after chronic exercise training

Change in biomarker Atg3 after chronic exercise training

Change in biomarker Atg5 after chronic exercise training

Change in biomarker Atg7 after chronic exercise training

Change in biomarker Lamp1 after chronic exercise training

Change in biomarker Lamp2 after chronic exercise training

Change in biomarker p62 after chronic exercise training

Secondary Outcome Measures

Change in radial arterial diameter after Rhythmic Handgrip Exercise

Change in radial arterial flow rate after Rhythmic Handgrip Exercise

Change in biomarker p-eNOSS1177 after Rhythmic Handgrip Exercise

Change in radial arterial diameter after chronic exercise training

Change in radial arterial flow rate after chronic exercise training

Change in biomarker p-eNOSS1177 after chronic exercise training

Full Information

NCT ID

NCT04200560

First Posted

June 18, 2019

Last Updated

August 19, 2022

Sponsor

University of Utah

1. Study Identification

Unique Protocol Identification Number

NCT04200560

Brief Title

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

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Completed

Study Start Date

July 1, 2018 (Actual)

Primary Completion Date

May 30, 2022 (Actual)

Study Completion Date

May 30, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Utah

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Vascular Diseases

Keywords

Aging, Endothelial Cell Autophagy

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Healthy Adult Subjects

Arm Type

Experimental

Arm Description

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

Arm Title

Healthy Older Adult Subjects

Arm Type

Experimental

Arm Description

Intervention Type

Other

Intervention Name(s)

Rhythmic Handgrip Exercise

Intervention Description

60 minute rhythmic handgrip exercise

Intervention Type

Other

Intervention Name(s)

Chronic Exercise Training

Intervention Description

Handgrip exercise training consisting of three 60-minute training sessions per week for eight weeks.

Primary Outcome Measure Information:

Title

Change in biomarker beclin-1 after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in biomarker Atg3 after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in biomarker Atg5 after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in biomarker Atg7 after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in biomarker Lamp1 after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in biomarker Lamp2 after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in biomarker p62 after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in biomarker beclin-1 after chronic exercise training

Time Frame

8 weeks

Title

Change in biomarker Atg3 after chronic exercise training

Time Frame

8 weeks

Title

Change in biomarker Atg5 after chronic exercise training

Time Frame

8 weeks

Title

Change in biomarker Atg7 after chronic exercise training

Time Frame

8 weeks

Title

Change in biomarker Lamp1 after chronic exercise training

Time Frame

8 weeks

Title

Change in biomarker Lamp2 after chronic exercise training

Time Frame

8 weeks

Title

Change in biomarker p62 after chronic exercise training

Time Frame

8 weeks

Secondary Outcome Measure Information:

Title

Change in radial arterial diameter after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in radial arterial flow rate after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in biomarker p-eNOSS1177 after Rhythmic Handgrip Exercise

Time Frame

60 min

Title

Change in radial arterial diameter after chronic exercise training

Time Frame

8 weeks

Title

Change in radial arterial flow rate after chronic exercise training

Time Frame

8 weeks

Title

Change in biomarker p-eNOSS1177 after chronic exercise training

Time Frame

8 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

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.

Facility Information:

Facility Name

VA Medical Center

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84148

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Upon written request, a limited, de-identified, anonymized dataset will be created pursuant to the Data use Agreement. This DUA will limit use of the dataset and prohibit the recipient from taking steps to identify individuals whose data is included in the dataset. This dataset will be provided through a password-protected, machine-readable database format. Whenever possible, the dataset will be delivered through physical transfer of a storage medium.

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

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