Background: Mitochondrial E3 ubiquitin ligase (MARCH5) as an important regulator in maintaining mitochondrial function. Our aims were to investigate the role and mechanism of MARCH5 in aortic valve calcification.
Methods: Human aortic valves, both calcified and non-calcified, were analyzed for MARCH5 expression using western blotting. Mitochondrial fragmentation was evaluated using transmission electron microscope. Osteogenic differentiation of human aortic valvular interstitial cells (HVICs) was induced with osteoblastic medium (OM), confirmed by western blotting and Alizarin red staining. Mitochondrial morphology and oxidative phosphorylation were assessed using MitoTracker and Seahorse, respectively. MARCH5-knockdown and ApoE-knockout mice fed high-fat diet were used to study aortic valve calcification.
Results: The mitochondrial quality control was impaired in calcified valves, and the level of MARCH5 protein was also decreased in calcified valves. Inhibition of MARCH5 impaired mitochondrial quality control, increased mitochondrial stress and accelerates osteogenic transformation in OM treated HVICs. While, overexpression MARCH5 has the opposite effects. Co-immunoprecipitation, mass spectrometry and molecular docking found MARCH5 interacted Rac GTPase-activating protein 1 (RACGAP1) and promoted its ubiquitination, leading to impaired mitochondrial quality control. Inhibiting RACGAP1 reversed osteogenic transformation induced by MARCH5 silencing in OM treated HVICs. Silencing dynamin-related protein 1 (DRP1) under RACGAP1 inhibition had no additional benefit. In vivo, deficiency of MARCH5 promoted aortic valve calcification, while inhibition RACGAP1 reversed aortic valve calcification in MARCH5 deficiency mice.
Conclusion: Downregulation of MARCH5 promotes RACGAP1 ubiquitination, activating DRP1 and impairing mitochondrial quality control, which contributes to aortic valve calcification. This identifies a potential therapeutic target for aortic valve calcification.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbamcr.2025.119911 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Murine Aortic Valve Cell Heterogeneity at Birth.
Arterioscler Thromb Vasc Biol
March 2025
Department of Pediatrics, Division of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee (T.B., J.R.K., A.J.K., J.L.).
Background: Heart valve function requires a highly organized ECM (extracellular matrix) network that provides the necessary biomechanical properties needed to withstand pressure changes during each cardiac cycle. Lay down of the valve ECM begins during embryogenesis and continues throughout postnatal stages when it is remodeled into stratified layers and arranged according to blood flow. Alterations in this process can lead to dysfunction and, if left untreated, heart failure.
View Article and Find Full Text PDFDecision making in surgery: honoring patient autonomy despite high mortality risk in a 36-year-old woman with endocarditis.
J Surg Case Rep
March 2025
Department of Palliative Care, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Infective endocarditis (IE) is a common complication in patients who inject drugs. We present the case of a 36-year-old woman with IE affecting both the aortic and tricuspid valves, along with a cardiac implantable electronic device infection, 11 weeks after combined aortic valve replacement, tricuspid valve replacement, and pacemaker implantation. The patient declined the medically indicated cardiac surgery due to her recent taxing surgical and rehabilitation experiences.
View Article and Find Full Text PDFSuccessful Valve-in-Valve-in-Valve Transcatheter Aortic Valve Implantation for Severe Bioprosthetic Valve Restenosis in a High-Risk Patient.
Cureus
February 2025
Cardiovascular Disease, University of Florida Health, Jacksonville, USA.
Transcatheter aortic valve implantation (TAVI) has significantly improved in treating aortic valve disease in recent years, particularly in patients at high surgical risk. This case report describes an 80-year-old woman who had severe aortic stenosis previously treated with surgical aortic valve replacement (SAVR) and six years later had a valve-in-valve (ViV) TAVI who developed severe symptomatic restenosis of the bioprosthetic aortic valve five years later of the last procedure. A third valve-in-valve-in-valve (ViViV) TAVI using a 26-mm Sapien 3 valve was performed due to the high surgical risk.
View Article and Find Full Text PDFTransradial Lower Limb Arteriography of the Type Ⅲ Aortic Arch: A Reverse Technique.
Cureus
February 2025
Cardiology, Akita Cerebrospinal and Cardiovascular Center, Akita, JPN.
Percutaneous coronary intervention is generally performed using the radial artery approach, and in recent years, the radial artery approach has also been used more and more for endovascular treatment. Given this trend, the radial artery approach is also preferable for lower limb angiography when considering patient burden. However, in the case of type III aortic arch morphology, it can be difficult to advance the catheter into the descending aorta using the radial artery approach.
View Article and Find Full Text PDFAcute Respiratory Distress Syndrome Following Minimally Invasive Cardiac Surgery.
Cureus
February 2025
Cardiovascular Surgery, Kyoto Prefectural University of Medicine, Kyoto, JPN.
Acute respiratory distress syndrome (ARDS) incidence following minimally invasive cardiac surgery (MICS) is rare. We report a case of acute respiratory failure following cardiac surgery that was diagnosed as ARDS. A 77-year-old female patient diagnosed with aortic valve stenosis underwent aortic valve replacement via a right thoracotomy.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!