Biology subjects

Heineke, J.

Publications and source records attributed to Heineke, J..

5 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

Loss of cardiomyocyte eukaryotic elongation factor 1 A2 in adult mice triggers cardiomyopathy due to defective proteostasis

Eukaryotic elongation factor 1A (eEF1A) delivers aminoacyl-tRNAs to ribosomes but also has additional, non-canonical functions. Mammals express two paralogs: eEF1A1 is ubiquitous, whereas eEF1A2 is confined to adult cardiomyocytes, skeletal myocytes, and neurons. Mutations in EEF1A2 cause cardiomyopathy, but underlying mechanisms remain unclear. Using adult, cardiomyocyte-specific Eef1a2 knock-out (Eef1a2-cKO) and Eef1a1/Eef1a2 double knock-out mice, we show that Eef1a2-cKO animals develop cardiomyopathy with increased mortality, systolic dysfunction, and fibrosis, despite unchanged global protein synthesis, while double knock-out mice die early in a sudden manner. Multi-omics analyses reveal post-transcriptional upregulation of ribosomal proteins and translational regulators in both models. Eef1a2-cKO hearts accumulate autophagosomes and protein aggregates, indicating defective autophagy. Mechanistically, we found that eEF1A2 functions as a chaperone supporting protein folding and proteostasis in cardiomyocytes. Early Rapamycin treatment (mTORC1 inhibition) normalizes systolic heart function and survival in Eef1a2-cKO mice and clears autophagosomes and protein aggregates. Thus, eEF1A2 maintains cardiac proteostasis, and mTORC1 inhibition may represent a therapeutic strategy for patients with EEF1A2 mutations.

physiology↗

bioRxiv2022

Secreted long non-coding RNAs Gadlor1 and Gadlor2 affect multiple cardiac cell types and aggravate cardiac remodeling during pressure overload

BackgroundPathological overload triggers maladaptive myocardial remodeling that leads to heart failure. Recent studies have shown that long non-coding RNAs (lncRNAs) regulate cardiac remodeling. This study investigates two recently discovered, secreted lncRNAs, Gadlor1 and Gadlor2 (Gadlor 1/2). MethodsWe generated compound Gadlor1/2 knock-out (KO) mice and compared their response to pressure overload by transverse aortic constriction (TAC) to that of wild-type (WT) littermates. Endothelial cells, fibroblasts and cardiomyocytes were isolated from the hearts of both genotypes after TAC and their transcriptome was investigated by RNA sequencing. Gadlor target proteins were identified by RNA antisense purification coupled with mass spectrometry (RAP-MS) in cardiomyocytes. In addition, we investigated the effects of cardiac overexpression of Gadlor1/2. ResultsGadlor1/2 are jointly upregulated in failing mouse hearts as well as in the myocardium of heart failure patients. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 KO mice, in turn, exerted markedly reduced myocardial hypertrophy, fibrosis and dysfunction, but more angiogenesis during short and long-standing pressure overload. Paradoxically, Gadlor1/2 KO mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. Gadlor1 and Gadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene-expression, are strongly secreted within extracellular vesicles (EVs). These EVs transfer Gadlor lncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, induce pro-hypertrophic gene-expression and enhance calcium re-uptake into the sarcoplasmic reticulum. ConclusionGadlor1 and Gadlor2 are lncRNAs that are mainly enriched in EC-derived EVs and are jointly upregulated in mouse and human hearts during pathological overload. We reveal a crucial endothelial cell-cardiomyocyte crosstalk, which aims at restoring calcium homeostasis in cardiomyocytes during overload at the cost of aggravated hypertrophy and fibrosis.

systems biology↗

bioRxiv2022

Rnf20 shapes the endothelial control of heart morphogenesis and function

During embryogenesis, distinct cardiac cell types form, which shape the structural and functional properties of the heart. How their activity is coordinated is largely unknown. Here we show that Rnf20 is a multifaceted regulator of cardiac morphogenesis and function. On the one hand, Rnf20 controls extracellular matrix dynamics and endothelial-cardiomyocyte crosstalk essential for second heart field development. On the other hand, it safeguards endothelial cell identity and function by maintaining physiological angiocrine signaling and preventing endothelial-to-mesenchymal transition. Endothelial-specific deletion of Rnf20 led to ventricular septal defects, myocardial thinning and cardiac dysfunction as a result of aberrant signaling and excessive extracellular matrix deposition that induced precocious cardiomyocyte binucleation and irregular contractility. Furthermore, we uncovered upstream factors (e.g. Sox9) and multiple angiocrine and extracellular matrix molecules that alter cardiomyocyte functionality upon endothelial Rnf20 loss. In summary, our work identifies a novel, endothelial-specific role of Rnf20 in regulating cardiac morphogenesis and function.

developmental biology↗

bioRxiv2018

Metformin Intervention Prevents Cardiac Dysfunction in a Murine Model of Adult Congenital Heart Disease

Congenital heart disease (CHD) is the most frequent birth defect worldwide and the number of adult patients with CHD, now referred to as ACHD, is increasing. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity and diabetes, is mostly unknown. Using a genetic mouse model of ACHD we showed that ACHD mice placed under metabolic stress (high fat diet) displayed decreased heart function. Comprehensive physiological, biochemical and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism that preceded cardiac dysfunction. Restoration of metabolic balance by metformin prevented the development of heart dysfunction in ACHD mice. This study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure and may be an important avenue for intervention in ACHD.

genetics↗