Talbot, C. C. | bioRxiv Science

bioRxiv2022

Hypereosinophilia causes progressive cardiac pathologies in mice

Hypereosinophilic syndrome is a progressive disease with extensive eosinophilia that results in organ damage. Cardiac pathologies are the main reason for its high mortality rate. A better understanding of the mechanisms of eosinophil-mediated tissue damage would benefit therapeutic development. Here, we describe the cardiac pathologies that developed in a mouse model of hypereosinophilic syndrome. These IL-5 transgenic mice exhibited decreased left ventricular function at a young age which worsened with age. Mechanistically, we demonstrated infiltration of activated eosinophils into the heart tissue that led to an inflammatory environment. Gene expression signatures showed tissue damage as well as repair and remodeling processes. Cardiomyocytes from IL-5Tg mice exhibited significantly reduced contractility relative to WT controls. This impairment may result from the inflammatory stress experienced by the cardiomyocytes and suggest that dysregulation of contractility and Ca2+ reuptake in cardiomyocytes contributes to cardiac dysfunction at the whole organ level in hypereosinophilic mice. TeaserToo many eosinophils cause inflammation in the heart and change cardiomyocyte contraction leading to poor heart function.

pathology↗

bioRxiv2020

Excessive O-GlcNAcylation causes heart failure and sudden death

BackgroundHeart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension and diabetes. O-GlcNAcylation, a post-translational modification of intracellular proteins, serves as a potent transducer of cellular stress. Failing myocardium is marked by increased O-GlcNAcylation, but it is unknown if excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure. The total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). MethodsWe developed two new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAclyation independent of pathological stress. ResultsWe found that OGT transgenic hearts showed increased O-GlcNAcylation, and developed severe dilated cardiomyopathy, ventricular arrhythmias and premature death. In contrast, OGA transgenic hearts had O-GlcNAcylation and cardiac function similar to wild type littermate controls. However, OGA trangenic hearts were resistant to pathological stress induced by pressure overload and had attenuated myocardial O-GlcNAcylation levels, decreased pathological hypertrophy and improved systolic function. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death despite persistant elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc mediated cardiac pathology. ConclusionsOur data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, due to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is an effective therapy against pressure overload induced heart failure. Attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LICardiomyopathy from diverse causes is marked by increased O-GlcNAcylation. Here we provide new genetic mouse models to control myocardial O-GlcNAcylation independent of pathological stress. C_LIO_LIGenetically increased myocardial O-GlcNAcylation causes progressive dilated cardiomyopathy and premature death, while genetic reduction of myocardial O-GlcNAcylation is protective against pathological hypertrophy caused by transaortic banding. C_LIO_LIExcessive myocardial O-GlcNAcylation decreases activity and expression of mitochondrial complex I. C_LI What are the clinical implications?O_LIIncreased myocardial O-GlcNAcylation has been shown to be associated with a diverse range of clinical heart failure including aortic stenosis, hypertension, ischemia and diabetes. C_LIO_LIUsing novel genetic mouse models we have provided new proof of concept data that excessive O-GlcNAcylation is sufficient to cause cardiomyopathy. C_LIO_LIWe have shown myocardial over-expression of O-GlcNAcase, an enzyme that reverses O-GlcNAcylation, is well tolerated at baseline, and improves myocardial responses to pathological stress. C_LIO_LIOur findings suggest reversing excessive myocardial O-GlcNAcylation could benefit diverse etiologies of heart failure. C_LI

molecular biology↗

bioRxiv2019

CaMKII oxidation is a performance/disease trade-off in vertebrate evolution

Reactive oxygen species (ROS) contribute to health and disease. CaMKII is a widely expressed enzyme whose activation by oxidation of regulatory domain methionines (ox-CaMKII) contributes to cardiovascular disease, asthma, and cancer. Here we integrate comparative genomic and experimental data to show that CaMKII activation by ROS arose more than half-a-billion years ago on the vertebrate stem lineage where it constituted a bridge between ROS and increased intracellular Ca2+ release, exercise responsive gene transcription, and improved performance in skeletal muscle. These enhancements to fight-or-flight physiology were likely key in facilitating a well-evidenced shift in the behavioural ecology of our immediate chordate ancestors, and, in turn, the evolutionary success of vertebrates. Still, the ox-CaMKII innovation for augmenting performance must be considered a critical evolutionary trade-off, as it rendered us more susceptible to common and often fatal diseases linked to excessive ROS.

evolutionary biology↗