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Introduction: N6-methyladenosine (m6A) methylation produces a marked effect on cardiovascular diseases. The m6A demethylase AlkB homolog 5 (ALKBH5), as an m6A "eraser", is responsible for decreased m6A modification. However, its role in cardiac fibroblasts during the post-myocardial infarction (MI) healing process remains elusive., Objectives: To investigate the effect of ALKBH5 in cardiac fibroblasts during infarct repair., Methods: MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets., Results: Dramatic alterations in ALKBH5 expression were observed during the early stages post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and ameliorated cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both in vivo and in vitro ALKBH5 loss resulted in impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-β1 or Ang II, upregulated ALKBH5 expression in myofibroblasts by HIF-1α-dependent transcriptional regulation. Mechanistically, ALKBH5 promoted the stability of ErbB4 mRNA and the degradation of ST14 mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout., Conclusion: Fibroblast ALKBH5 positively regulates post-MI healing by stabilization of ErbB4 mRNA in an m6A-dependent manner. ALKBH5/ErbB4 might be potential therapeutic targets for post-MI cardiac rupture., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Cardiac fibrosis is a common feature of various cardiovascular diseases. Previous studies showed that acetaldehyde dehydrogenase 2 (ALDH2) deficiency exacerbated pressure overload-induced heart failure. However, the role and mechanisms of cardiac fibrosis in this process remain largely unknown. This study aimed to investigate the effect of ALDH2 deficiency on cardiac fibrosis in transverse aortic constriction (TAC) induced pressure overload model in mice. Echocardiography and histological analysis revealed cardiac dysfunction and enhanced cardiac fibrosis in TAC-operated animals; ALDH2 deficiency further aggravated these changes. ALDH2 chimeric mice were generated by bone marrow (BM) transplantation of WT mice into the lethally irradiated ALDH2KO mice. The proportion of circulating fibroblast progenitor cells (FPCs) and ROS level in BM after TAC were significantly higher in ALDH2KO mice than in ALDH2 chimeric mice. Furthermore, FPCs were isolated and cultured for in vitro mechanistic studies. The results showed that the stem cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor 4 (CXCR4) axis played a major role in the recruitment of FPCs. In conclusion, our research reveals that increased bone marrow FPCs mobilization and myocardial homing contribute to the enhanced cardiac fibrosis and dysfunction induced by TAC in ALDH2 KO mice via exacerbating accumulation of ROS in BM and myocardial SDF-1 expression., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

• H-151 treatment can preserve myocardial function and attenuate cardiac fibrosis in murine myocardial infarction. • H-151 treatment can inhibit the cGAS-STING-IRF3 pathway and inflammation in macrophages infiltrated in heart during myocardial infarction. • H-151 treatment can inhibit the type I interferon response in bone marrow-derived macrophages elicited by dsDNA extracted from hearts. • H-151 treatment on macrophages can decrease the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts. During myocardial infarction (MI), the stimulation of the cGAS-STING-IRF3 pathway in infiltrated macrophages can induce the apoptosis of cardiomyocytes and the fibrosis of cardiac fibroblasts, while H-151 is reported as a selective STING inhibitor. We intended to use H-151 to alleviate MI injury. Male C57BL/6J mice were subjected to induce MI, while H-151 (750 nmol) were used for treatment. Myocardial function was assessed through echocardiology and cardiac fibrosis was evaluated by Masson's Trichrome-staining. The stimulation of the STING pathway and the aggravation of inflammation was assessed by levels of protein and mRNA. BMDMs were stimulated by dsDNA extracted from the murine heart, while H-151 was used as treatment. After co-culturing adult cardiomyocytes and cardiac fibroblasts with supernatant of BMDMs, the apoptosis of adult cardiomyocytes and the fibrosis of cardiac fibroblasts was assessed. H-151 treatment showed significant function in preserving myocardial function and decreasing cardiac fibrosis 28 days after MI. H-151 treatment showed significant function in inhibiting the cGAS-STING-IRF3 pathway and inflammation, especially type I interferon response. H-151 could alleviate the type I interferon response in BMDMs elicited by cardiac dsDNA, and thus H-151 could attenuate the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts after co-culturing them with the supernatant of BMDMs. H-151, a selective inhibitor of the cGAS-STING-IRF3 pathway, can preserve myocardial function and alleviate cardiac fibrosis after MI by inhibiting the type I interferon response in infiltrated macrophages triggered by cardiac dsDNA which increase the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts. [ABSTRACT FROM AUTHOR]