Role of human epicardial adipose tissue–derived miR-92a-3p in myocardial redox state
<p><strong>Background</strong><br> Visceral obesity is directly linked to increased cardiovascular risk, including heart failure.<br><br> <strong>Objectives</strong><br> This study explored the ability of human epicardial adipose tissue (EAT)-de...
| Hoofdauteurs: | , , , , , , , , , , , , , |
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| Formaat: | Journal article |
| Taal: | English |
| Gepubliceerd in: |
Elsevier
2023
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| _version_ | 1826310448853549056 |
|---|---|
| author | Carena, MC Badi, I Polkinghorne, M Akoumianakis, I Psarros, C Wahome, E Kotanidis, CP Akawi, N Antonopoulos, AS Chauhan, J Douglas, G Channon, KM Casadei, B Antoniades, A |
| author_facet | Carena, MC Badi, I Polkinghorne, M Akoumianakis, I Psarros, C Wahome, E Kotanidis, CP Akawi, N Antonopoulos, AS Chauhan, J Douglas, G Channon, KM Casadei, B Antoniades, A |
| author_sort | Carena, MC |
| collection | OXFORD |
| description | <p><strong>Background</strong><br>
Visceral obesity is directly linked to increased cardiovascular risk, including heart failure.<br><br>
<strong>Objectives</strong><br>
This study explored the ability of human epicardial adipose tissue (EAT)-derived microRNAs (miRNAs) to regulate the myocardial redox state and clinical outcomes.<br><br>
<strong>Methods</strong><br>
This study screened for miRNAs expressed and released from human EAT and tested for correlations with the redox state in the adjacent myocardium in paired EAT/atrial biopsy specimens from patients undergoing cardiac surgery. Three miRNAs were then tested for causality in an in vitro model of cardiomyocytes. At a clinical level, causality/directionality were tested using genome-wide association screening, and the underlying mechanisms were explored using human biopsy specimens, as well as overexpression of the candidate miRNAs and their targets in vitro and in vivo using a transgenic mouse model. The final prognostic value of the discovered targets was tested in patients undergoing cardiac surgery, followed up for a median of 8 years.<br><br>
<strong>Results</strong><br>
EAT miR-92a-3p was related to lower oxidative stress in human myocardium, a finding confirmed by using genetic regulators of miR-92a-3p in the human heart and EAT. miR-92a-3p reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase–derived superoxide (O2.–) by targeting myocardial expression of WNT5A, which regulated Rac1-dependent activation of NADPH oxidases. Finally, high miR-92a-3p levels in EAT were independently related with lower risk of adverse cardiovascular events.<br><br>
<strong>Conclusions</strong><br>
EAT-derived miRNAs exert paracrine effects on the human heart. Indeed miR-92a-3p suppresses the wingless-type MMTV integration site family, member 5a/Rac1/NADPH oxidase axis and improves the myocardial redox state. EAT-derived miR-92a-3p is related to improved clinical outcomes and is a rational therapeutic target for the prevention and treatment of obesity-related heart disease.</p> |
| first_indexed | 2024-03-07T07:52:11Z |
| format | Journal article |
| id | oxford-uuid:d6f2d596-f2db-4848-88ea-efae14ae543f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:52:11Z |
| publishDate | 2023 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:d6f2d596-f2db-4848-88ea-efae14ae543f2023-07-19T09:44:31ZRole of human epicardial adipose tissue–derived miR-92a-3p in myocardial redox stateJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d6f2d596-f2db-4848-88ea-efae14ae543fEnglishSymplectic ElementsElsevier2023Carena, MCBadi, IPolkinghorne, MAkoumianakis, IPsarros, CWahome, EKotanidis, CPAkawi, NAntonopoulos, ASChauhan, JDouglas, GChannon, KMCasadei, BAntoniades, A<p><strong>Background</strong><br> Visceral obesity is directly linked to increased cardiovascular risk, including heart failure.<br><br> <strong>Objectives</strong><br> This study explored the ability of human epicardial adipose tissue (EAT)-derived microRNAs (miRNAs) to regulate the myocardial redox state and clinical outcomes.<br><br> <strong>Methods</strong><br> This study screened for miRNAs expressed and released from human EAT and tested for correlations with the redox state in the adjacent myocardium in paired EAT/atrial biopsy specimens from patients undergoing cardiac surgery. Three miRNAs were then tested for causality in an in vitro model of cardiomyocytes. At a clinical level, causality/directionality were tested using genome-wide association screening, and the underlying mechanisms were explored using human biopsy specimens, as well as overexpression of the candidate miRNAs and their targets in vitro and in vivo using a transgenic mouse model. The final prognostic value of the discovered targets was tested in patients undergoing cardiac surgery, followed up for a median of 8 years.<br><br> <strong>Results</strong><br> EAT miR-92a-3p was related to lower oxidative stress in human myocardium, a finding confirmed by using genetic regulators of miR-92a-3p in the human heart and EAT. miR-92a-3p reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase–derived superoxide (O2.–) by targeting myocardial expression of WNT5A, which regulated Rac1-dependent activation of NADPH oxidases. Finally, high miR-92a-3p levels in EAT were independently related with lower risk of adverse cardiovascular events.<br><br> <strong>Conclusions</strong><br> EAT-derived miRNAs exert paracrine effects on the human heart. Indeed miR-92a-3p suppresses the wingless-type MMTV integration site family, member 5a/Rac1/NADPH oxidase axis and improves the myocardial redox state. EAT-derived miR-92a-3p is related to improved clinical outcomes and is a rational therapeutic target for the prevention and treatment of obesity-related heart disease.</p> |
| spellingShingle | Carena, MC Badi, I Polkinghorne, M Akoumianakis, I Psarros, C Wahome, E Kotanidis, CP Akawi, N Antonopoulos, AS Chauhan, J Douglas, G Channon, KM Casadei, B Antoniades, A Role of human epicardial adipose tissue–derived miR-92a-3p in myocardial redox state |
| title | Role of human epicardial adipose tissue–derived miR-92a-3p in myocardial redox state |
| title_full | Role of human epicardial adipose tissue–derived miR-92a-3p in myocardial redox state |
| title_fullStr | Role of human epicardial adipose tissue–derived miR-92a-3p in myocardial redox state |
| title_full_unstemmed | Role of human epicardial adipose tissue–derived miR-92a-3p in myocardial redox state |
| title_short | Role of human epicardial adipose tissue–derived miR-92a-3p in myocardial redox state |
| title_sort | role of human epicardial adipose tissue derived mir 92a 3p in myocardial redox state |
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