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Project description:Background: Post-infarction heart failure is attributed to ischemia-induced myocardial inflammation and unfavorable remodeling, with reparative macrophages playing a crucial role in limiting excessive fibrosis and promoting cardiac repair via cytokine secretion and cross-cell interactions. Hence, a timely and adequate transition of macrophage phenotypes is essential for proper wound healing post-MI, but the precise mechanisms underlying this process remain incompletely elucidated. Methods: To elucidate the function of NPM1 in post-infarct cardiac repair, we generated macrophage-specific NPM1 knockout mouse models. Additionally, Cut&Tag assays were conducted on cardiac macrophages for the first time to explore the epigenetic mechanisms underlying NPM1-mediated regulation of macrophage metabolic reprogramming. Results: Macrophage-specific deletion of NPM1 in MI mouse models resulted in reduced tissue fibrosis and enhanced cardiac repair by promoting the phenotypic transition of macrophages towards a reparative state. NPM1 deletion also led to a shift in macrophage metabolism from glycolysis to mitochondrial OXPHOS via inactivation of the mTOR cascades. Mechanistically, we demonstrated that IL-4 induced NPM1 oligomerization, which recruited histone demethylase KDM5b to the promoter region of Tsc1, ultimately leading to macrophage metabolic rewiring. Antisense oligonucleotides and inhibitory compounds targeting NPM1 exhibited notable protective effects on cardiac repair post-MI. Conclusions: Our study demonstrates that NPM1 may serve as a promising prognostic biomarker and a valuable therapeutic target for ischemia-induced heart failure, shedding new light on the understanding of post-infarct cardiac repair and may pave the way for the development of innovative therapeutic strategies.
2026-01-26 | GSE230944 | GEO
Project description:Background: Post-infarction heart failure is attributed to ischemia-induced myocardial inflammation and unfavorable remodeling, with reparative macrophages playing a crucial role in limiting excessive fibrosis and promoting cardiac repair via cytokine secretion and cross-cell interactions. Hence, a timely and adequate transition of macrophage phenotypes is essential for proper wound healing post-MI, but the precise mechanisms underlying this process remain incompletely elucidated. Methods: To elucidate the function of NPM1 in post-infarct cardiac repair, we generated macrophage-specific NPM1 knockout mouse models. Additionally, Cut&Tag assays were conducted on cardiac macrophages for the first time to explore the epigenetic mechanisms underlying NPM1-mediated regulation of macrophage metabolic reprogramming. Results: Macrophage-specific deletion of NPM1 in MI mouse models resulted in reduced tissue fibrosis and enhanced cardiac repair by promoting the phenotypic transition of macrophages towards a reparative state. NPM1 deletion also led to a shift in macrophage metabolism from glycolysis to mitochondrial OXPHOS via inactivation of the mTOR cascades. Mechanistically, we demonstrated that IL-4 induced NPM1 oligomerization, which recruited histone demethylase KDM5b to the promoter region of Tsc1, ultimately leading to macrophage metabolic rewiring. Antisense oligonucleotides and inhibitory compounds targeting NPM1 exhibited notable protective effects on cardiac repair post-MI. Conclusions: Our study demonstrates that NPM1 may serve as a promising prognostic biomarker and a valuable therapeutic target for ischemia-induced heart failure, shedding new light on the understanding of post-infarct cardiac repair and may pave the way for the development of innovative therapeutic strategies.
2026-01-26 | GSE230938 | GEO
Project description:Pro-inflammatory and reparative macrophages are crucial in clearing necrotic myocardium and promoting cardiac repair after myocardial infarction (MI), respectively. Extracellular adenosine has been demonstrated to modulate macrophage polarization through adenosine receptors. However, the role of intracellular adenosine in macrophage polarization has not been explored and adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels. Here, we aimed to elucidate the role of ADK in macrophage polarization and its subsequent impact on MI. We demonstrated that ADK was upregulated in bone marrow-derived macrophages (BMDMs) after IL-4 treatment and was highly expressed in the infarct area at day 7 post-MI, especially in macrophages. Compared with wild-type mice, myeloid-specific Adk knockout mice showed increased infarct size, limited myofibroblast differentiation, reduced collagen deposition and more severe cardiac dysfunction after MI, which was related to impaired reparative macrophage phenotype in MI tissue. We found that ADK deletion or inhibition significantly decreased the expression of reparative genes, such as Arg1, Ym1, Fizz1, and Cd206 in BMDMs after IL-4 treatment. The increased intracellular adenosine due to Adk deletion inhibited transmethylation reactions and decreased the trimethylation of H3K4 in BMDMs after IL-4 treatment. Mechanistically, we demonstrated that Adk deletion suppressed reparative macrophage phenotype through decreased IRF4 expression, which resulted from reduced levels of H3K4me3 on the Irf4 promotor. Together, our study reveals that ADK exerts a protective effect against MI by promoting reparative macrophage polarization through epigenetic mechanisms.
| S-EPMC10420407 | biostudies-literature
Project description:Targeting NPM1 Epigenetically Promotes Post-infarction Cardiac Repair by Reprogramming Reparative Macrophage Metabolism
| PRJNA962923 | ENA
Project description:Targeting NPM1 Epigenetically Promotes Post-infarction Cardiac Repair by Reprogramming Reparative Macrophage Metabolism [RNA-Seq]
| PRJNA962932 | ENA
Project description:Targeting NPM1 Epigenetically Promotes Post-infarction Cardiac Repair by Reprogramming Reparative Macrophage Metabolism [CUT&Tag]
| PRJNA962931 | ENA
Project description:Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis and metabolism, but how it modulates myocardial infarction remains unclear. In this study, we showed that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Using RNA-seq, protein and molecular docking, and Targeted Metabolomics (LC-MS), our data demonstrated that macrophages expressing TREM2 exhibited decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD+ transport into mitochondria, downregulated SLC25A53 thereby causing the breakpoint in the TCA cycle and subsequently increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2+ macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages could improve cardiac function. In summary, our study reveals a novel role for macrophage-specific TREM2 in MI, connecting efferocytosis to immune metabolism during cardiac repair.
| S-EPMC10850484 | biostudies-literature
Project description:We want to find that the TREM2 mechanism on the Macrophages in the myocardial infarction
2022-11-15 | GSE218002 | GEO
Project description:Neonatal mammalian heart maintains a transient regeneration capacity after birth, whereas this regeneration ability gradually loses in the postnatal heart. Thus, the reactivation of cardiomyocyte proliferation is emerging as a key strategy for inducing heart regeneration in adults. We have reported that a highly conserved long noncoding RNA (lncRNA) LncDACH1 was overexpressed in the failing hearts. Here, we found that LncDACH1 was gradually upregulated in the postnatal hearts. Cardiac-specific overexpression of LncDACH1 (TG) in mice suppressed neonatal heart regeneration and worsened cardiac function after apical resection. Conversely, in vivo cardiac conditional knockout of LncDACH1 (CKO) and adenovirus-mediated silencing of endogenous LncDACH1 reactivated cardiomyocyte-proliferative potential and promoted heart regeneration after myocardial infarction (MI) in juvenile and adult mice. Mechanistically, LncDACH1 was found to directly bind to protein phosphatase 1 catalytic subunit alpha (PP1A), and in turn, limit its dephosphorylation activity. Consistently, PP1A siRNA or pharmacological blockers of PP1A abrogated cardiomyocyte mitosis induced by LncDACH1 silencing. Furthermore, LncDACH1 enhanced yes-associated protein 1 (YAP1) phosphorylation and reduced its nuclear translocation by binding PP1A. Verteporfin, a YAP1 inhibitor decreased LncDACH1 silencing-induced cardiomyocyte proliferation. In addition, targeting a conserved fragment of LncDACH1 caused cell cycle re-entry of human iPSC-derived cardiomyocytes. Collectively, LncDACH1 governs heart regeneration in postnatal and ischemic hearts via regulating PP1A/YAP1 signal, which confers a novel therapeutic strategy for ischemic heart diseases.
| S-EPMC7308407 | biostudies-literature
Project description:RationaleAdoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application, despite limited mechanistic understanding of the endogenous response after myocardial infarction (MI). Extracellular matrix undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair.ObjectiveTo demonstrate the significance of fibronectin (Fn), a component of the extracellular matrix, for induction of the endogenous CPC response to MI.Methods and resultsThis report shows that presence of CPCs correlates with the expression of Fn during cardiac development and after MI. In vivo, genetic conditional ablation of Fn blunts CPC response measured 7 days after MI through reduced proliferation and diminished survival. Attenuated vasculogenesis and cardiogenesis during recovery were evident at the end of a 12-week follow-up period. Impaired CPC-dependent reparative remodeling ultimately leads to continuous decline of cardiac function in Fn knockout animals. In vitro, Fn protects and induces proliferation of CPCs via β₁-integrin-focal adhesion kinase-signal transducer and activator of transcription 3-Pim1 independent of Akt.ConclusionsFn is essential for endogenous CPC expansion and repair required for stabilization of cardiac function after MI.
| S-EPMC3815660 | biostudies-literature