Autophagy, Oxidative Stress and Hippo Signaling in Human Aortic Aneurysm

April 8, 2022 updated by: Maurizio Forte, Neuromed IRCCS

Study of the Molecular Mechanisms Associated With the Formation of Human Aortic Aneurysm: a Focus on Autophagy, Oxidative Stress and Hippo Signaling

The molecular mechanisms contributing to the development of aortic aneurysmal disease are poorly characterized making actual therapies not sufficient. Autophagy is an intracellular mechanism that removes dysfunctional organelles and unfolded proteins, thereby maintaining cellular homeostasis. Activation of autophagy was shown to limit cardiac damage during stress. Accordingly, autophagy was found to be inhibited in the heart in animal models of metabolic syndrome, diabetes, obesity and aging thereby contributing to the development of cardiac derangements associated with these conditions. However, it remains to fully dissect the association between autophagy and structural alterations of the aortic wall and endothelial dysfunction in humans. In this study the correlation between levels of autophagy and the development of human aortic aneurysm will be assessed in patients subjected to surgical interventions for aortic pathologies. The association of Hippo signaling activation with the formation of aortic disease will also be evaluated, since previous work demonstrated that the Hippo pathway negatively regulates autophagy and promotes the development of cellular abnormalities. The results of this study may provide new insights into the mechanisms underlying the development of aortic disease.

Study Overview

Status

Completed

Conditions

Detailed Description

Autophagy may represent a new potential therapeutic target for the prevention and the treatment of aortic pathologies. It is a cellular self- digestion mechanism that prevents the accumulation of senescent organelles and damaged proteins. Autophagy plays a pivotal role in the regulation of cellular homeostasis and promotes the cellular response to stress. However, further investigations are needed to establish how autophagy is influenced by cardiovascular risk factors, as well as by pharmacological therapy. Moreover, it is still unclear in humans the association between autophagy and structural and functional alterations of aortic wall, as well as its association with endothelial dysfunction, especially in subjects affected by aortic pathologies. Furthermore, no data are available on the correlation between autophagy and the prognosis of patients who underwent cardio-surgical procedures for aortic pathologies. In this study, autophagy levels will be evaluated in human aortic aneurysm samples obtained from patients enrolled for a surgical aorta procedures. Autophagy markers in each aneurysm sample will be compared to those observed in the non-aneurysmatic aortic portion adjacent to the aneurysmatic tract obtained from the same patient. Levels of autophagy will also be correlated with markers of apoptosis and oxidative stress in both the aneurysmatic and non-aneurysmatic aortic parts. The involvement of the Hippo signaling pathway and inflammation in control and aneurysm samples will also be investigated. The investigators expect that autophagy levels will be lower in aneurysm samples with respect to non-aneurysmatic adjacent aortic portions. They will also be inversely correlated with aneurysm dimension. In contrast, the Hippo pathway will be activated in aortic aneurysms. Autophagy and Hippo signaling markers will also be correlated with markers of apoptosis and oxidative stress in aortic samples. In conclusion, the results of this study may underline the vascular role of autophagy and Hippo signaling and their involvement in the development of aortic diseases.

Study Type

Observational

Enrollment (Actual)

30

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Isernia
      • Pozzilli, Isernia, Italy
        • IRCCS Neuromed

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Subjects affected by abdominal aortic aneurysms undergoing aortic surgical procedures

Description

Inclusion Criteria:

  • Eligible subjects undergoing aortic surgical procedures
  • Ejection fraction (FE) > 30%
  • Acceptance and signature of the informed consent

Exclusion Criteria:

  • Acute myocardial infarction in the last 6 months
  • Chronic and acute Inflammatory diseases
  • Immunological and rheumatic diseases
  • Pre-existing or ongoing neoplasms
  • infectious diseases
  • Treatment with pharmacological therapies able to modulate autophagy, i. e. rapamycin and derivative compounds (rapalogues))
  • Antioxidant therapies in the last three months
  • Patients with surgical technical complications

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Comparison between the levels of Hippo signaling and autophagy markers observed in aortic aneurysms and the levels assessed in the adjacent non-aneurysmatic aortic portions.
Time Frame: 1 month
Quantification by immunoblot of markers of Hippo signaling (MST1, YAP) and autophagy (LC3, p62, Beclin1, Atg5, Atg7, Ulk1. Adjacent aortic fragments without aneurysm belonging to the same patient will be used as control.
1 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Impact of cardiovascular risk factors on the autophagy levels in aortic samples of patients undergoing surgical procedure of aortic aneurysm removal.
Time Frame: 1 month
Quantification by immunoblot of markers of autophagy (LC3, p62, Beclin1, Atg5, Atg7, Ulk1) and its statistical correlation with cardiovascular risk factors, such as age, diabetes, obesity, hypercholesterolemia, metabolic syndrome
1 month
Correlation between levels of autophagy and apoptosis in aneurysmal samples
Time Frame: 1 month
Quantification by immunoblot of markers of autophagy and apoptosis
1 month
Correlation between levels of autophagy and endothelial function in patients undergoing surgical procedure of aortic aneurysm removal
Time Frame: 1 month
flow- mediated dilatation (FMD) in subject underwent surgical procedure of aortic substitution/dissection
1 month
Correlation between levels of autophagy and the size of aortic aneurysms
Time Frame: 1 month
Aneurysmal dimension will be evaluated by CT angiography
1 month

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation between autophagy, oxidative stress and inflammation
Time Frame: 1 month
western blot for markers of autophagy, ELISA and High Performance Liquid Chromatography (HPLC) analyses for markers of oxidative stress
1 month
Correlation between levels of autophagy and the Hippo pathway
Time Frame: 1 month
western blot for marker of autophagy and the Hippo pathway
1 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Principal Investigator: Giacomo Frati, MD, IRCCS Neuromed

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 1, 2017

Primary Completion (ACTUAL)

October 31, 2017

Study Completion (ACTUAL)

November 1, 2017

Study Registration Dates

First Submitted

July 5, 2017

First Submitted That Met QC Criteria

July 5, 2017

First Posted (ACTUAL)

July 7, 2017

Study Record Updates

Last Update Posted (ACTUAL)

April 11, 2022

Last Update Submitted That Met QC Criteria

April 8, 2022

Last Verified

April 1, 2022

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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