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Johny, E.

Publications and source records attributed to Johny, E..

3 recordsLinked to original sources
bioRxiv2026

Myeloid STING restrains cardiac remodeling by suppressing macrophage amyloid precursor protein

Mitochondrial DNA (mtDNA) released into the cytosol activates innate immune signaling and promotes inflammation, yet its role in macrophages following sterile tissue injury remains poorly understood. Here, we show that cardiac macrophages from both patients and mice with myocardial infarction (MI) exhibit increased mitochondrial biogenesis, mitochondrial content, membrane potential, and expression of mitochondrial nucleases that facilitate mtDNA release. Consistently, macrophage-specific silencing of genes regulating mitochondrial biogenesis or mtDNA processing attenuated adverse cardiac remodeling after MI. Unexpectedly, despite the role of mtDNA in activating the cGAS-STING pathway, myeloid deletion or macrophage-specific silencing of Sting or cGas exacerbated ventricular dilation, fibrosis, and contractile dysfunction following MI. Single-cell transcriptomic and cell communication analyses identified amyloid precursor protein (APP) as a key downstream effector of STING in cardiac macrophages. Macrophage-specific in vivo App silencing rescued the detrimental effects of myeloid Sting deficiency, establishing APP as a critical mediator of adverse remodeling. Mechanistically, STING interacted with the transcriptional repressor MZF1, promoted its nuclear localization, facilitated its binding to the App promoter, and suppressed App transcription to restrain adverse cardiac remodeling. Together, our findings uncover an unexpected cardioprotective function of myeloid STING and identify the STING-MZF1-APP axis as a previously unrecognized mechanism governing cardiac repair after myocardial infarction.

cell biology↗
bioRxiv2026

Humanin analogue promotes metabolic reprogramming to protect the ischemic heart

BackgroundMyocardial ischemia drives adverse cardiac remodeling, metabolic inflexibility, and progression to heart failure. Mitochondrial dysfunction and impaired substrate utilization contribute to cardiomyocyte death and fibrosis, particularly with aging. Humanin (HNG), a mitochondria-derived peptide, has been shown to reduce acute ischemic injury, but its role in chronic ischemia and cardiac remodeling remains unknown. MethodsWe investigated the effects of HNG treatment in young and aged murine models of myocardial ischemia without reperfusion. Cardiac function and structure were assessed by echocardiography and molecular markers of remodeling. Myocardial metabolism was interrogated using targeted metabolomics, gene expression, substrate uptake assays, and metabolic flux analyses. Mechanistic studies examined glucose transporter trafficking and protein-protein interactions. ResultsHNG treatment improved cardiac function and significantly attenuated adverse remodeling in both young and old mice. HNG treatment induced marked metabolic reprogramming characterized by reduced myocardial fatty acid content, downregulation of fatty acid uptake and oxidation pathways, and decreased oxidative stress. Importantly, these changes were accompanied by enhanced glucose oxidation, increased tricarboxylic acid cycle flux, improved coupling of glycolysis to mitochondrial oxidation, and increased ATP production. Time-course studies demonstrated that increased glucose oxidation preceded reductions in fatty acid oxidation, indicating a primary role for glucose metabolism in HNG-mediated cardioprotection. Mechanistically, we identified vesicle-associated membrane protein 7 (VAMP7) as a novel binding partner of HNG, and that this interaction is required for GLUT4 translocation to the plasma membrane and HNG-induced ATP generation. ConclusionsHNG protects the ischemic heart by promoting metabolic reprogramming that shifts substrate utilization from fatty acids to glucose and limiting maladaptive remodeling. These findings identify HNG as a novel regulator of cardiac metabolism and a potential therapeutic strategy for ischemic heart failure. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/732776v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1929de8org.highwire.dtl.DTLVardef@bcf254org.highwire.dtl.DTLVardef@c99b70org.highwire.dtl.DTLVardef@1fc08bb_HPS_FORMAT_FIGEXP M_FIG C_FIG What are the clinical implications?Heart failure (HF) is a major global health concern, affecting over 6.7 million adults in the United States alone, with projections to exceed 11 million by 2050. Myocardial infarction (MI) is a leading cause of HF. Despite substantial advances in acute MI care, survivors remain at high risk for adverse cardiac remodeling and chronic HF, especially in the elderly. We report here that treatment with a potent analog of Humanin (HN), an endogenous mitochondria-associated peptide, decreases infarct size, decreases fibrosis and improves cardiac function following cardiac ischemia induced by permanent ligation of coronary artery in both young and aged mice. These effects are associated with changes in cardiac metabolism, oxidative stress, and remodeling. HN and analogs have been shown to be beneficial in many age-related diseases. The endogenous origin of Humanin, its favorable safety profile in preclinical studies and its pleiotropic effects support targeting HNG as a promising therapeutic strategy for ischemic heart disease and post-myocardial infarction heart failure in humans.

Systems Biology↗
bioRxiv2025

Activated fatty acid synthesis pathway in macrophages propagates pathogenic fibroblast expansion after myocardial infarction

Metabolic pathways, such as fatty acid oxidation and oxidative phosphorylation, can modulate inflammatory cells. However, little is known about the effects of the fatty acid synthesis pathway in macrophages on inflammation and cardiac remodeling after myocardial infarction (MI). Using spatial metabolomics, here we show that cardiac macrophages residing in the infarct synthesize de novo fatty acids and increase the production of fatty acid enzymes including ACLY and FASN. Mice deficient in myeloid Acly and Fasn have improved cardiac function after MI and reduced fibrosis. Combining Cleavage Under Targets and Release Using Nuclease (CUT&RUN), RNA sequencing analysis of Acly-/-macrophages, and macrophage-specific in vivo gene silencing, we demonstrate that ACLY acetylates the promoter region of the upstream regulator Krt17, which drives the production of pro-fibrotic cytokines, including IL-33. Single-cell RNA sequencing of cardiac fibroblasts shows that the expansion of a population of fibroblasts (Fibroblast 5) expressing high levels of extracellular matrix genes after MI is confined in the absence of macrophage Acly. Finally, the analysis of spatial multi-omics data of human hearts with MI uncovers myofibroblasts with the Fibroblast 5 gene signature. These myofibroblasts are located near cardiac macrophages expressing high levels of ACLY. In summary, we show that macrophage ACLY and FASN are deleterious in MI pathogenesis.

immunology↗