2025 Hyper Recent •CC0 1.0 Universal

This work is dedicated to the public domain. No rights reserved.

Access Preprint From Server
July 18th, 2025
Version: 1
Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Dise
molecular biology
biorxiv

Myocyte Enhancer Factor 2A Orchestrates Vascular Redox Homeostasis via Direct Transcriptional Activation of SIRT1

Liu, B.Open in Google Scholar•Fang, L.Open in Google Scholar•Miao, C.Open in Google Scholar•Wen, X.Open in Google Scholar•Zheng, X.Open in Google Scholar•Xu, M.Open in Google Scholar•Lin, J.Open in Google Scholar•Xiong, Y.Open in Google Scholar•Liu, S.-M.Open in Google Scholar

Myocyte enhancer factor 2A (MEF2A), a transcription factor implicated in coronary artery disease, remains unexplored in vascular redox regulation. To address this gap and overcome limitations of current antioxidant therapies, we investigated MEF2A's role in oxidative defense using human umbilical vein endothelial cells (HUVECs) and murine models. Adenoviral vectors encoding MEF2A-specific shRNA or mRNA were employed to silence or overexpress MEF2A in HUVECs. For in vivo validation, endothelial-targeted MEF2A knockdown was achieved via AAV1-shRNA delivery in mice fed a high-fat diet. Systemic redox status was assessed by measuring reactive oxygen species (ROS), glutathione homeostasis (GSH/GSSG ratio), NADH/NAD+ balance, mitochondrial membrane potential, and 8-OHdG. Mechanistic insights were derived from immunofluorescence, qPCR, western blotting, and dual-luciferase reporter assays. MEF2A silencing induced redox imbalance, characterized by elevated ROS, reduced GSH/GSSG ratio, and mitochondrial membrane potential collapse. Conversely, MEF2A overexpression synergized with SIRT1 to restore glutathione pools, maintain NAD+ homeostasis, and suppress ROS under oxidative stress. Chromatin immunoprecipitation confirmed direct MEF2A binding to two cis-elements in the SIRT1 promoter, driving transcriptional activation. In vivo, MEF2A-deficient mice exhibited amplified vascular oxidative damage, including elevated DNA damage marker (8-OHdG) and ROS levels. Downregulation of SIRT1/PGC-1a; in MEF2A silenced cells was verified in vivo. Our findings establish MEF2A as a master regulator of endothelial redox defense via the SIRT1-PGC-1a; axis, offering a mechanistic foundation for targeting oxidative cardiovascular disorders. This work suggests pharmacological MEF2A activation as a novel strategy for precision antioxidant therapy in vascular medicine.

Similar Papers

biorxiv
Fri Jul 18 2025
How many (distinguishable) classes can we identify in Single Particle Analysis?
Heterogeneity in cryoEM is essential for capturing macromolecule structural variability, reflecting their functional states and biological significance. However, estimating heterogeneity remains challenging due to particle misclassification and algorithmic biases, which can lead to reconstructions that blend distinct conformations or fail to resolve subtle differences. Furthermore, the low signal-...
Lauzirika, O.
•
Pernica, M.
•
Herreros, D.
•
Ramirez, E.
...•
Sorzano, C. O. S.
biorxiv
Fri Jul 18 2025
Impact of Sugar-Based Baits on Midgut Microbiome Composition in Aedes Mosquitoes: Implications for Vector Control
Many severe mosquito-borne diseases are transmitted by the Aedes sp. mosquitoes. Control efforts have been strengthened by the implementation of novel integrated vector management techniques such as alginate hydrogel beads and appealing toxic sugar bait. These techniques help to control mosquitoes by taking advantage of their attraction to sugar. Different types of sugar that mosquitoes ingest dur...
Sambanthan, R.
•
ABU KASSIM, N. F.
•
Abuelmaali, S. A.
•
Kamil, W. M. W. A.
...•
Webb, C. E.
biorxiv
Fri Jul 18 2025
Whole blood transcriptional signatures of age and survival identified in Long Life Family and Integrative Longevity Omics Studies
Background. Age is one of the major risk factors for a wide range of diseases. Nevertheless, some individuals can better cope with these changes and become centenarians. We hypothesize that their blood transcriptome may provide insights into the mechanisms contributing to healthy aging, as well as enable the discovery of candidate therapeutic targets. The Long-Life Family Study (LLFS), which inclu...
Li, M.
•
Song, Z.
•
Reed, E.
•
Karagiannis, T. T.
...•
Monti, S.
biorxiv
Fri Jul 18 2025
Humanized mice enable in vivo evaluation of engineered plasma cell biology and therapeutic function
Engineered plasma cells (ePCs) offer a durable strategy for in vivo delivery of therapeutic antibodies, but standard immunodeficient mouse models lack human immune factors critical for plasma cell survival and function. We utilized a humanized mouse model in which NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were engrafted with human CD34+ stem cells as recipients for infusions with autologous ePCs...
Hill, T. F.
•
Helmers, A. E.
•
Cheng, R. Y.
•
Singh, S.
...•
James, R. G.
biorxiv
Fri Jul 18 2025
Sustained Yap/Taz activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling
YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and incre...
Gaona, I. P.
•
McCall, A. S.
•
Geis, N. M.
•
Colvard, A. C.
...•
Gokey, J. J.
biorxiv
Fri Jul 18 2025
Targeted Whole Genome Sequencing of African Swine Fever Virus and Classical Swine Fever Virus on the MinION Portable Sequencing Platform
African swine fever virus (ASFV) and classical swine fever virus (CSFV) are important transboundary animal diseases (TADs) affecting swine. ASFV is a large DNA virus with a genome size of 170-190 kilobases (kB) belonging to the family Asfarviridae, genus Asfivirus. CSFV is a single-stranded RNA virus with genome size of approximately 12 kB belonging to the family Flaviviridae, genus Pestivirus. Ou...
McDowell, C. D.
•
Kwon, T.
•
Assato, P.
•
Mantlo, E.
...•
Richt, J. A.
biorxiv
Fri Jul 18 2025
Bidirectional control of a metabolic transition by the GID ubiquitin ligase
The GID/CTLH ubiquitin ligase is a multisubunit E3 conserved across eukaryotes. GID/CTLH has been implicated in a variety of processes, including metabolic regulation, cell proliferation, embryonic development and cell differentiation. However, our understanding of substrate recognition by GID/CTLH remains incomplete. Here, we characterize the regulation, specificity and functions of the putative ...
Kong, K.-Y. E.
•
Ochs, C.
•
Debarnot, C.
•
Myllykoski, M.
...•
Khmelinskii, A.
biorxiv
Fri Jul 18 2025
An Unexpected Role of Molecular Chaperones in Regulating the Excited States and Activities of Folded Enzymes
Emerging evidence suggests that chaperones not only facilitate the folding of nascent polypeptides but also interact with quasi-native or natively folded proteins. However, the biological significance of these interactions remains unclear. In our previous study, we demonstrated that the molecular chaperone-like protein BSA reshapes the energy landscape of folded client proteins, increasing the pop...
Wang, G.
•
Bin, Y.
•
Chen, Y.
•
Ding, R.
...•
He, L.
biorxiv
Fri Jul 18 2025
Genome-Wide Investigation of Transcription Factor Occupancy and Dynamics Using cFOOT-seq
Gene regulation relies on the precise binding of transcription factors (TFs) at regulatory elements, but simultaneously detecting hundreds of TFs on chromatin is challenging. We developed cFOOT-seq, a cytosine deaminase-based TF footprinting assay, for high-resolution, quantitative genome-wide assessment of TF binding in both open and closed chromatin, even with small cell numbers. By utilizing th...
Wang, H.
•
Wu, A.
•
Yang, M.-C.
•
Zhou, D.
...•
Zhang, J.-m.