Chronic O-GlcNAcylation and Diabetic Cardiomyopathy: The Bitterness of Glucose

Abstract

Type 2 diabetes (T2D) is a major risk factor for heart failure. Diabetic cardiomyopathy (DC) is characterized by diastolic dysfunction and left ventricular hypertrophy. Epidemiological data suggest that hyperglycaemia contributes to the development of DC. Several cellular pathways have been implicated in the deleterious effects of high glucose concentrations in the heart: oxidative stress, accumulation of advanced glycation end products (AGE), and chronic hexosamine biosynthetic pathway (HBP) activation. In the present review, we focus on the effect of chronic activation of the HBP on diabetic heart function. The HBP supplies N-acetylglucosamine moiety (O-GlcNAc) that is O-linked by O-GlcNAc transferase (OGT) to proteins on serine or threonine residues. This post-translational protein modification modulates the activity of the targeted proteins. In the heart, acute activation of the HBP in response to ischaemia-reperfusion injury appears to be protective. Conversely, chronic activation of the HBP in the diabetic heart affects Ca2+ handling, contractile properties, and mitochondrial function and promotes stress signaling, such as left ventricular hypertrophy and endoplasmic reticulum stress. Many studies have shown that O-GlcNAc impairs the function of key protein targets involved in these pathways, such as phospholamban, calmodulin kinase II, troponin I, and FOXO1. The data show that excessive O-GlcNAcylation is a major trigger of the glucotoxic events that affect heart function under chronic hyperglycaemia. Supporting this finding, pharmacological or genetic inhibition of the HBP in the diabetic heart improves heart function. In addition, the SGLT2 inhibitor dapagliflozin, a glucose lowering agent, has recently been shown to lower cardiac HBP in a lipodystophic T2D mice model and to concomitantly improve the diastolic dysfunction of these mice. Therefore, targeting cardiac-excessive O-GlcNAcylation or specific target proteins represents a potential therapeutic option to treat glucotoxicity in the diabetic heart.

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

“…Such a finding is consistent with the fact that no other class of antihyperglycaemic drugs reduces the risk of serious heart failure events, even though other glucose‐lowering drugs achieve comparable or greater decreases in glycated haemoglobin . Furthermore, in the DAPA‐HF trial, the benefits of dapagliflozin on the progression of heart failure were seen both in patients with or without diabetes, and the magnitude of benefit was not enhanced in diabetic patients, thus undermining the hypothesis that mitigation of glycaemia‐related cardiotoxicity was responsible for the amelioration of the progression of heart failure . Additionally, it is unlikely that heart failure events are reduced by an action of SGLT2 inhibitors to prevent acute coronary occlusive events, since these drugs do not decrease the risk of myocardial infarction, and conversely, antihyperglycaemic drugs that primarily act to prevent coronary atherosclerotic events do not have favourable effects on the evolution of heart failure …”

Excess Protein O-GlcNAcylation Links Metabolic Derangements to Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

“…To further explore the potential link between O-GlcNAcylation and right ventricular function, we examined the effects of diabetes on right ventricular function in PAH patients ( Table 2 ) because diabetes is a disease of excess cardiomyocyte O-GlcNAcylation [ 12 , 13 , 14 ]. There was a significant, negative relationship between right ventricular contractility and HgbA1C levels in PAH patients ( r = −0.52, p = 0.02) ( Figure 5 A).…”

“…OGA removes GlcNAc from proteins and thus reverses O-GlcNAcylation [ 9 ]. While O-GlcNAcylation is elevated in diabetic cardiomyopathy [ 12 , 13 , 14 ] and chronic excess O-GlcNAcylation causes mitochondrial dysfunction [ 14 , 15 , 16 ], the role of O-GlcNAcylation in RVD in PAH is unexplored. Importantly, previous work shows that one of the major causes of RVD in PAH relates to mitochondrial metabolic dysfunction [ 17 , 18 , 19 ].…”

“…We then examined the therapeutic implications of AMP-kinase activation, using colchicine, on HBP intermediate levels, O-GlcNAcylation, the right ventricle’s metabolic signature and function in both models. Finally, in PAH patients we examined the relationship between diabetes, a condition characterized by excess cardiac O-GlcNAcylation [ 12 , 13 , 14 ], and right ventricular function. We discovered that O-GlcNAcylation is increased in both experimental and human PAH and predicts right ventricular dysfunction.…”

Diabetic Cardiomyopathy and Ischemic Heart Disease: Prevention and Therapy by Exercise and Conditioning

“…The production of endogenous AGE is the result of a non-enzymatic reaction between glucose and proteins and lipids and plays an important role in the pathogenesis of cardiovascular diseases, nephropathy, diabetic retinopathy, and neuropathy, together with the aging process [10,19]. The increase in AGE levels, The hexosamine biosynthesis pathway promotes the protein O-GlcNAcylation, altering important cellular functions, including calcium handling, mitochondrial, and contractile machinery [16][17][18]. The production of endogenous AGE is the result of a non-enzymatic reaction between glucose and proteins and lipids and plays an important role in the pathogenesis of cardiovascular diseases, nephropathy, diabetic retinopathy, and neuropathy, together with the aging process [10,19].…”