Abstract
<title>Abstract</title> <p>Background The incidence of heart failure is approximately 2.5-fold higher in patients with type 2 diabetes than in non-diabetic individuals. Diabetic cardiomyopathy is characterized by diastolic dysfunction and left ventricular hypertrophy. The diabetic heart exhibits insulin resistance, leading to impaired glucose uptake and oxidation and, consequently, to intracellular glucose overload and glucotoxic stress. To further investigate the mechanisms underlying diabetic cardiomyopathy, we have previously examined the cardiac phenotype of lipodystrophic and severely insulin-resistant seipin knockout mice. These mice developed left ventricular hypertrophy associated with chronic activation of the hexosamine biosynthetic pathway, which promotes over-O-GlcNAcylation of cardiac proteins. Methods To assess the causal role of chronic activation of the hexosamine biosynthetic pathway in cardiac dysfunction in seipin knockout mice, we used adeno-associated virus-mediated cardiac overexpression of O-GlcNAcase, the enzyme responsible for removing O-GlcNAc moieties. Cardiac properties were evaluated by echocardiography. O-GlcNAcylated proteins were enriched using wheat germ agglutinin pull-down followed by proteomic analysis. Pharmacological inhibition and genetic modulation were used to investigate the role of β-catenin signalling. Results Cardiac overexpression of O-GlcNAcase corrected cardiac hypertrophy, as assessed by echocardiography, and improved insulin sensitivity in seipin knockout hearts. Proteomic analyses identified 28 proteins with increased O-linked N-acetylglucosamine modification in seipin knockout mice. Among these, β-catenin emerged as a candidate mediator, as expression of its target genes was increased in seipin knockout mice and normalized upon O-GlcNAcase overexpression. Increased β-catenin activity was associated with enhanced O-GlcNAcylation. Pharmacological inhibition of β-catenin using ICG-001 prevented cardiac hypertrophy in seipin knockout mice. Increased β-catenin O-GlcNAcylation and activity were also observed in two other murine models of diabetic cardiomyopathy. Selective enhancement of β-catenin O-GlcNAcylation was sufficient to induce hypertrophy in cultured cardiomyocytes. Conclusion These findings indicate that β-catenin O-GlcNAcylation contributes to cardiac remodelling in insulin-resistant states. This mechanism may extend beyond the seipin deficient specific model and could represent a potential target for the treatment of cardiac hypertrophy associated with type 2 diabetes.</p>