ExcessiveO- GlcNAcylation causes heart failure and sudden death
Authors: Umapathi Priya , Banerjee Partha S. , Zachara Natasha E. , Abrol Neha , Wang Qinchuan , Mesubi Olurotimi O. , Luczak Elizabeth D. , Wu Yuejin , Granger Jonathan M. , Wei An-Chi , Reyes Gaido Oscar E. , Florea Liliana , Talbot C. Conover , Hart Gerald W. , Anderson Mark E. 
Published: February 2020

Background

Heart 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 increasedO-GlcNAcylation, but it is unknown if excessiveO-GlcNAcylation contributes to cardiomyopathy and heart failure. The total levels ofO-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of two enzymes,O-GlcNAc transferase (OGT) andO-GlcNAcase (OGA).

Methods

We developed two new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAclyation independent of pathological stress.

Results

We found that OGT transgenic hearts showed increasedO-GlcNAcylation, and developed severe dilated cardiomyopathy, ventricular arrhythmias and premature death. In contrast, OGA transgenic hearts hadO-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 myocardialO-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 inO-GlcNAc mediated cardiac pathology.

Conclusions

Our data provide evidence that excessiveO-GlcNAcylation causes cardiomyopathy, at least in part, due to defective energetics. Enhanced OGA activity is well tolerated and attenuation ofO-GlcNAcylation is an effective therapy against pressure overload induced heart failure. Attenuation of excessiveO-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.

Clinical Perspective

What is new?

Cardiomyopathy from diverse causes is marked by increasedO-GlcNAcylation. Here we provide new genetic mouse models to control myocardialO-GlcNAcylation independent of pathological stress.

Genetically increased myocardialO-GlcNAcylation causes progressive dilated cardiomyopathy and premature death, while genetic reduction of myocardialO-GlcNAcylation is protective against pathological hypertrophy caused by transaortic banding.

Excessive myocardialO-GlcNAcylation decreases activity and expression of mitochondrial complex I.

What are the clinical implications?

Increased myocardialO-GlcNAcylation has been shown to be associated with a diverse range of clinical heart failure including aortic stenosis, hypertension, ischemia and diabetes.

Using novel genetic mouse models we have provided new proof of concept data that excessiveO-GlcNAcylation is sufficient to cause cardiomyopathy.

We have shown myocardial over-expression ofO-GlcNAcase, an enzyme that reversesO-GlcNAcylation, is well tolerated at baseline, and improves myocardial responses to pathological stress.

Our findings suggest reversing excessive myocardialO-GlcNAcylation could benefit diverse etiologies of heart failure.