Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway

Shi, Ying; Zhao, Lili; Zhang, Yifei; Qin, Qin; Cong, Hongliang; Guo, Zhigang

doi:10.21037/atm-21-5602

Cited by 8 publications

(5 citation statements)

References 35 publications

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“…In addition, ACS-EVs induced a targeted modulation of SRC, NOTCH1, FOXO3, BAIAP2, CDC42, IKBKG, RXRA, DGKG, SYP, CHL1, and SHB genes. As previously reported, NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, SRC genes are already involved in CVDs [41,42,[44][45][46][47]51,53,59,62]. In particular, we observed that FOXO3 showed significant hypo-methylated CpGs in the 5 ′ UTR and exon regions (start108561195 -end108561194) (q value 2.99E-04) and a corresponding significant transcript overexpression in PBMC ACS-EVs treated (p<0.05).…”

Section: Discussionsupporting

confidence: 76%

“…Our cardiovascular sub-network was characterized by 41 nodes and 29 edges with PPI enrichment p value of 0.000101 (average node degree of 1.41 and average local clustering coefficient of 0.344), where the hub DMG was the proto-oncogene tyrosine-protein kinase Src (SRC) and the PPIs connected others 10 hub DMGs: Notch Receptor 1 (NOTCH1), Forkhead Box O3 (FOXO3), brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2), Cell Division Cycle 42 (CDC42), inhibitor of nuclear factor kappa B kinase regulatory subunit gamma (IKBKG), retinoid X receptor alpha (RXRA), diacylglycerol kinase gamma (DGKG), synaptophysin (SYP), cell adhesion molecule L1 like (CHL1), and SH2 domain containing adaptor protein B (SHB). Among all these genes, only for some (NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, BAIAP2) there is molecular evidence of their involvement in CVD, such as hypertension, cardiac remodelling, vascular smooth muscle cells (VSMCs) and endothelial cell (ECs) differentiation [43][44][45][46][47][48][49][50][51][52][53].…”

Section: Ppi Network Construction Of Dmgsmentioning

confidence: 99%

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De novo DNA methylation induced by circulating extracellular vesicles from acute coronary syndrome patients

et al. 2022

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Section: Discussionsupporting

confidence: 76%

Section: Ppi Network Construction Of Dmgsmentioning

confidence: 99%

De novo DNA methylation induced by circulating extracellular vesicles from acute coronary syndrome patients

et al. 2022

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“…Furthermore, we were able to locate 16 trials reporting cardiac fibrosis as a result of Hcy-induced oxidative stress [ 41 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. Several mechanisms of action have been proposed for this effect, including increased reactive oxygen species, nitrotyrosine, matrix metalloproteinase, and decreased endothelial nitric oxide in response to antagonizing PPAR-gamma [ 82 ] and regulation of the Akt/FoxO3 pathway.…”

Section: Resultsmentioning

confidence: 99%

Homocysteine as a Predictor of Paroxysmal Atrial Fibrillation-Related Events: A Scoping Review of the Literature

et al. 2022

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High levels of homocysteine (Hcy) have been linked with adverse cardiovascular outcomes, such as arrhythmias and stroke. In the context of paroxysmal atrial fibrillation (PAF), hyperhomocysteinemia has been demonstrated to be an independent predictor of future events. The aim of this report was to address the potential value of Hcy levels in predicting future paroxysms of atrial fibrillation (AF), as well as to identify the potential mechanisms of action. We searched PubMed and the Cochrane Database on 16 January 2022. Keywords used were homocysteine or hyperhomocysteinemia paired with a total of 67 different keywords or phrases that have been implicated with the pathogenesis of AF. We included primary reports of clinical and non-clinical data in the English language, as well as systematic reviews with or without meta-analyses. We placed no time constraints on our search strategy, which yielded 3748 results. Following title review, 3293 reports were excluded and 455 reports were used for title and abstract review, after which 109 reports were finally used for full-text review. Our review indicates that Hcy levels seem to hold a predictive value in PAF. Herein, potential mechanisms of action are presented and special considerations are made for clinically relevant diagnostic procedures that could complement plasma levels in the prediction of future PAF events. Finally, gaps of evidence are identified and considerations for future clinical trial design are presented.

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“…We identified a significant disruption in ECM homeostasis following PKP2 knockdown, potentially due to the upregulation of Foxo3, a key transcription factor known to promote ECM degradation. The activation of Foxo3 has been reported to enhance the degradation of ECM components, such as fibronectin (FN1), in endothelial cells and cardiac fibroblasts 16 , vascular smooth muscle 17 and cardiac fibroblast 18 . In our study, the upregulated Foxo3 was associated with a significant downregulation of FN1 and fibrinogens, indicating a potential mechanism for ECM remodeling in ARVC.…”

Section: Discussionmentioning

confidence: 99%

Multiomics Analysis Reveals Extensive Remodeling of the Extracellular Matrix and Cellular Metabolism Due to Plakophilin-2 Knockdown in Guinea Pigs

Song,

Wu,

et al. 2024

Preprint

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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death (SCD) in young individuals, yet the mechanisms underlying its pathogenesis, particularly the role of plakophilin-2 (PKP2), remain incompletely understood. This study aimed to elucidate the profile of molecular and metabolic consequences of PKP2 knockdown in a guinea pig model of ARVC. We employed adeno-associated virus serotype 9 (AAV9) to deliver PKP2 shRNA, establishing a model that recapitulates key features of human ARVC, including right ventricular (RV) enlargement, sudden death, and cardiac lipid accumulation. Proteomic analysis revealed significant dysregulation of extracellular matrix (ECM) proteins, PI3K-Akt signaling, and energy metabolism in PKP2-deficient RVs. Metabolomic profiling further highlighted alterations in lipid metabolism and inter-metabolites of TCA cycle, with a notable shift towards fatty acid oxidation. These findings suggest that PKP2 deficiency triggers a cascade of molecular events leading to ECM remodeling, metabolic reconfiguration, and potential mitochondrial dysfunction, which may contribute to the development of ARVC. Our study provides novel insights into the early molecular mechanisms of ARVC and identifies potential therapeutic targets for this underexplored disease.

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Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway

Cited by 8 publications

References 35 publications

De novo DNA methylation induced by circulating extracellular vesicles from acute coronary syndrome patients

De novo DNA methylation induced by circulating extracellular vesicles from acute coronary syndrome patients

Homocysteine as a Predictor of Paroxysmal Atrial Fibrillation-Related Events: A Scoping Review of the Literature

Multiomics Analysis Reveals Extensive Remodeling of the Extracellular Matrix and Cellular Metabolism Due to Plakophilin-2 Knockdown in Guinea Pigs

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