Biology subjects

Rangrez, A. Y.

Publications and source records attributed to Rangrez, A. Y..

3 recordsLinked to original sources

bioRxiv2026

FYCO1 improves postischemic cardiac remodeling via enhanced autophagic flux and attenuation of proinflammatory signaling

Acute myocardial infarction (MI) is associated with severe metabolic and oxidative stress that triggers cardiomyocyte death, pro-inflammatory signaling and progressive structural remodeling frequently culminating in heart failure. Although significant advances in reperfusion therapy improved acute survival in patients, therapeutic strategies that directly target intracellular processes in response to injury remain limited. One key response mechanism, autophagy, is rapidly activated to ameliorate ischemic stress. Yet, defective autophagic flux may exacerbate cardiomyocyte injury and maladaptive tissue remodeling. Here we identify FYCO1 as a cardiomyocyte-enriched key regulator of autophagy that enhances autophagic flux and promotes myocardial resilience following ischemic injury. Using cardiomyocyte-specific FYCO1 transgenic mice subjected to permanent coronary ligation, we demonstrate that FYCO1 overexpression limits infarct expansion, reduces cardiomyocyte injury, and preserves cardiac function during remodeling. In vivo RFP-EGFP-LC3 autophagy reporter analyses reveal that FYCO1 promotes a sustained increase of autophagic flux by coordinating autophagosome formation and efficient autolysosomal clearance. Transcriptomic profiling identifies a cardioprotective gene program in FYCO1-Tg animals subjected to MI, with suppression of proinflammatory, proapoptotic and stress-response pathways. Systemic serum cytokine and chemokine profiling as well as transcriptomic analyses of myocardium confirm reduced inflammatory signaling and subsequent reduction in macrophage recruitment into the infarct border zone. Together these findings position FYCO1 as a key regulator of cardiomyocyte autophagy and reveal a previously unrecognized link between autophagy and inflammation in shaping cardiac remodeling following myocardial infarction. FYCO1-mediated autophagy promotes myocardial preservation and functional recovery, highlighting autophagic flux as a promising target for cardioprotective interventions.

molecular biology↗

bioRxiv2026

Multicellular signaling and partial recovery define reverse cardiac remodeling

Heart failure results from maladaptive multicellular remodeling triggered by sustained biomechanical stress. Although mechanical unloading can promote reverse remodeling, recovery is frequently incomplete and its mechanistic basis remains unclear. Using a reversible murine pressure-overload model combined with bulk and single-nucleus transcriptomics, we demonstrate that reverse remodeling represents an actively maintained yet constrained multicellular state. Unloading improved cardiac function and partially restored extracellular matrix and metabolic programs, whereas inflammatory and mitochondrial dysfunction signatures persisted. Cardiomyocytes and endothelial cells largely re-established homeostatic transcriptional states, while fibroblasts retained activated programs that dominated residual pathology. Multicellular factor analysis delineated a reversible metabolic stress program and a persistent inflammatory-mitochondrial program coordinated across cardiac cell types. Cell-cell communication analysis identified lymphatic endothelial cells as key instructive regulators of recovery. Notably, lymphatic-derived Reelin directly suppressed pathological fetal gene activation in murine and human cardiomyocytes, uncovering a previously unrecognized lymphoangiocrine mechanism that constrains myocardial recovery in chronic heart failure.

molecular biology↗

bioRxiv2025

TRIM24 preserves cardiomyocyte immune quiescence by repressing interferon/STAT signaling

Innate immune activation in cardiomyocytes is a key driver of inflammatory heart disease and heart failure progression, yet the mechanisms by which cardiomyocytes maintain transcriptional immune quiescence remain poorly understood. TRIM24, a multidomain chromatin reader implicated in cancer and inflammation, has not been previously studied in the heart. Here, we investigated whether TRIM24 regulates interferon/STAT-driven inflammatory programs and paracrine signaling in cardiomyocytes. Single-nucleus RNA sequencing revealed a pronounced downregulation of TRIM24 specifically in cardiomyocytes from human ischemic cardiomyopathy, a change not detected by bulk RNA-sequencing in either human or mouse myocardial infarction samples, likely due to masking by non-cardiomyocyte cell populations. Fractionated protein analysis further demonstrated that TRIM24 is enriched in cardiomyocyte nuclei. Functional studies in neonatal rat ventricular cardiomyocytes showed that TRIM24 represses interferon-stimulated and STAT-dependent genes, including Mx1, Irf7, and Ifit3. ChIP-Seq revealed TRIM24 occupancy at STAT-bound regulatory regions, suggesting cooperative suppression of inflammatory gene networks. Mechanistically, TRIM24 decreased Stat1a/b and Stat3 transcription, reduced protein abundance, and inhibited phosphorylation independently of proteasomal degradation; these effects were partially reversible by bromodomain inhibition. Functionally, TRIM24 overexpression dampened paracrine macrophage recruitment, whereas TRIM24 depletion amplified it. Collectively, these findings identify TRIM24 as a cardiomyocyte-enriched chromatin regulator that restrains STAT1/3 signaling and suppresses paracrine inflammatory activation. TRIM24 acts as a transcriptional safeguard of immune quiescence in the heart and represents a potential therapeutic target for limiting cardiac inflammation.

molecular biology↗