DOI: 10.1161/circ.148.suppl_1.14526 ISSN: 0009-7322

Abstract 14526: CREG1 Deletion Inhibits Autophagy and Causes Cardiomyocyte Damage Under Nutritional Stress

Russell J Pepe, Yanmei Qi, Leonard Y Lee, Shaohua Li
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Introduction: The cellular repressor of E1A-stimulated genes 1 (CREG1) is a small, highly conserved glycoprotein ubiquitously expressed in mammalian tissues. It localizes in the endosomal-lysosomal compartment and promotes lysosome biogenesis and acidification. The goal of the current study was to elucidate the physiological function of CREG1 in the mouse heart.

Hypothesis: We hypothesized that deletion of Creg1 would result in pathological cardiac remodeling following nutritional stress.

Methods: We generated whole-body and cardiomyocyte-specific Creg1 KO mouse lines via mating Creg1 fl/fl mice with UBC-Cre-ERT2 and Myh6-Cre mice, respectively. Mice were fasted for 16-40 hours, and hearts were evaluated by H&E staining, immunofluorescence, electron microscopy, and biochemical analysis. Knockout mice were compared to within-litter controls.

Results: Under ad lib feeding, some whole-body knockout mice exhibited myofibril disarray and irregular nuclei in the heart. After prolonged fasting, both whole-body and cardiomyocyte-specific deletion of Creg1 resulted in significantly increased intracellular vacuoles, pale cytoplasm, and loss of nuclei in the papillary muscles and interventricular septa ( Figure 1 ). Immunofluorescence staining demonstrated significantly increased size and number of LC3 puncta (an autophagosome marker), and Western blot demonstrated accumulation of LC3II in the Creg1 KO hearts. In Creg1 KO cardiomyocytes, electron microscopy revealed condensed and irregular mitochondria, which lost their registry with myofibers. In addition, mitophagy was impaired and sarcomeric Z-discs were either damaged or obliterated.

Conclusion: CREG1 protects the heart from nutritional stress-induced injury, likely through the promotion of autophagic flux.

More from our Archive