Biology subjects

Glinton, K.

Publications and source records attributed to Glinton, K..

4 recordsLinked to original sources

bioRxiv2026

The Neonatal Myeloid Hypoxia Response Promotes a Cardiac Regenerative Response through Insulin-Like Growth Factor

BackgroundThe adult mammalian heart lacks the regenerative potential required to replenish depleted cardiomyocytes and restore cardiac function after injury. Ischemic cardiac injury contributes to heart failure, a leading cause of death worldwide. Neonatal mice possess the capacity to regenerate injured myocardium and macrophages contribute to this process. The mechanisms contributing to the regenerative crosstalk between macrophages and cardiomyocytes remain incompletely elucidated and offer potential to inform future therapeutic strategies. MethodsTo test the immune contribution during cardiac regeneration, we studied the response to myocardial ischemia in neonatal mice after silencing myeloid hypoxia inducible factor 1 (Hif1) and reconstituting HIF-dependent mitogens. In parallel, we examined epigenetic and transcriptional signatures of the cardiac macrophage response and focused on intercellular crosstalk with cardiomyocytes. ResultsIn myeloid Hif1 deficient mice, cardiac regenerative function was lost after coronary ligation. This manifested through loss of ventricular systolic function and elevated myocardial scarring. HIF1 was found to be activated in resident-type cardiac macrophages after ischemic insult. Hypoxia stimulated macrophages to secrete insulin-like growth factor 1 (IGF-1), and this required Hif1. Parallel multiomic analysis revealed epigenetic regenerative signatures. ConclusionsThe data reveal an age-restricted requirement for myeloid Hif1 in neonatal cardiac regeneration, likely through IGF-1 signaling.

immunology↗

bioRxiv2025

LncRNA H19 Upregulation Links Hypoplastic Left Heart Syndrome to Impaired PINK1/Parkin-Mediated Mitophagy and Ischemic Vulnerability

BACKGROUNDThe myocardium in hypoplastic left heart syndrome (HLHS) exhibits immature metabolic programming, impaired mitochondrial quality control, and heightened susceptibility to ischemic and hypoxic injury during palliative surgery. The long non-coding RNA H19 suppresses translation of PTEN-induced putative kinase 1 (PINK1) mRNA and modulates mitochondrial quality control and ischemia/reperfusion injury (IRI) in adult hearts. Whether--and how--H19 regulates mitophagy and IRI in HLHS or in immature animals remains unknown. METHODSWe investigated H19 regulation and its role in mitophagy and ischemia/reperfusion or hypoxia/reoxygenation injury in myocardial tissue from HLHS patients, HLHS-specific induced pluripotent stem cell-derived cardiomyocytes (HLHS-iPSC-CMs), and immature rat hearts. Mechanistic interactions among H19, PINK1/Parkin signaling, and mitophagosome formation were assessed using loss-of-function approaches. RESULTSHLHS myocardium exhibited markedly elevated H19 expression, accompanied by reduced PINK1 and Parkin protein abundance and diminished mitophagosome formation. Similar findings were observed in HLHS-iPSC-CMs exposed to hypoxia/reoxygenation and in immature rat hearts subjected to myocardial IRI. H19 knockdown in HLHS-iPSC-CMs attenuated hypoxia/reoxygenation-induced lactate dehydrogenase release and restored PINK1 and Parkin protein levels. In immature rats, myocardial H19 silencing reduced infarct size, enhanced mitochondrial PINK1 and Parkin expression, and improved post-reperfusion cardiac function for up to 28 days. Conversely, knockdown of PINK1 or Parkin reduced mitophagosome formation and exacerbated functional deterioration during IRI. CONCLUSIONSH19 upregulation impairs PINK1/Parkin-dependent mitophagy and increases susceptibility to ischemic and hypoxic injury in HLHS and the immature heart. These findings identify H19 as a key regulator of mitochondrial quality control and a potential therapeutic target for mitigating IRI in early-life cardiac disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/694773v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@193defdorg.highwire.dtl.DTLVardef@114ce7forg.highwire.dtl.DTLVardef@1010d05org.highwire.dtl.DTLVardef@1fdeac1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIThe myocardium in hypoplastic left heart syndrome (HLHS) exhibits immature metabolic programming, abnormal coronary perfusion, and impaired mitochondrial quality control, rendering it highly susceptible to ischemic and hypoxic injury. C_LIO_LIBoth structural limitations and intrinsic mitochondrial dysfunction contribute to the reduced ischemic tolerance of the HLHS heart, particularly during surgical and hemodynamic stress. C_LIO_LIThe long noncoding RNA H19 regulates mitochondrial quality control and modulates myocardial ischemia/reperfusion injury (IRI) in adult hearts. C_LIO_LIH19 inhibits the binding of the translation initiation factor eIF4A2 to PTEN-induced putative kinase 1 (PINK1) mRNA, thereby suppressing PINK1 protein synthesis and influencing PINK1-dependent mitophagy in adult mice. C_LI What New Information Does This Article Contribute?O_LIThis study identifies robust upregulation of H19 in HLHS myocardium, HLHS-specific induced pluripotent stem cell-derived cardiomyocytes (HLHS-iPSC-CMs) exposed to hypoxia/reoxygenation, and in immature rats subjected to myocardial IRI. C_LIO_LIElevated H19 is associated with suppressed PINK1/Parkin-dependent mitophagy, exacerbated IRI, and adverse post-injury remodeling. C_LIO_LIKnockdown of H19 restores mitochondrial PINK1 and Parkin protein levels, enhances mitophagy, reduces infarct size, and improves long-term recovery of cardiac function--demonstrating a previously unrecognized pathogenic role for H19 in the immature heart under stress. C_LIO_LIKnockdown of PINK1 or Parkin decreases mitophagosomes and exacerbates myocardial IRI in immature rats. C_LI

genomics↗

bioRxiv2024

HIF-1alpha is Required to Differentiate the Neonatal Macrophage Secretome from Adults

The immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages polarized to an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent on hypoxia inducible transcription factor-1 (HIF-1). In contrast, adult macrophages adopted a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age and HIF-1 dependent macrophage programs that may be targeted to calibrate the innate immune response during stress and inflammation.

immunology↗

bioRxiv2021

Bone Marrow-Derived AXL Tyrosine Kinase Promotes Mitogenic Crosstalk and Cardiac Allograft Vasculopathy

Cardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derived Axl gene, we report that Axl antagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses of Axl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions of Axl uncovered complementary cell-proliferative pathways by which Axl promotes CAV-associated inflammation. Specifically, Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered that Axl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloid Axl in the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.

immunology↗