Abstract
Diabetic heart disease is a distinct clinical entity that can progress to heart failure and sudden death. However, the mechanisms responsible for the alterations in excitation-contraction coupling leading to cardiac dysfunction during diabetes are not well known. Hyperglycemia, the landmark of diabetes, leads to the formation of advanced glycation end products (AGEs) on long-lived proteins, including sarcoplasmic reticulum (SR) Ca2+ regulatory proteins. However, their pathogenic role on SR Ca2+ handling in cardiac myocytes is unknown. Therefore, we investigated whether an AGE cross-link breaker could prevent the alterations in SR Ca2+ cycling that lead to in vivo cardiac dysfunction during diabetes. Streptozotocin-induced diabetic rats were treated with alagebrium chloride (ALT-711) for 8 weeks and compared to age-matched placebo-treated diabetic rats and healthy rats. Cardiac function was assessed by echocardiographic examination. Ventricular myocytes were isolated to assess SR Ca2+ cycling by confocal imaging and quantitative Western blots. Diabetes resulted in in vivo cardiac dysfunction and ALT-711 therapy partially alleviated diastolic dysfunction by decreasing isovolumetric relaxation time and myocardial performance index (MPI) (by 27 and 41% vs. untreated diabetic rats, respectively, P < 0.05). In cardiac myocytes, diabetes-induced prolongation of cytosolic Ca2+ transient clearance by 43% and decreased SR Ca2+ load by 25% (P < 0.05); these parameters were partially improved after ALT-711 therapy. SERCA2a and RyR2 protein expression was significantly decreased in the myocardium of untreated diabetic rats (by 64 and 36% vs. controls, respectively, P < 0.05), but preserved in the treated diabetic group compared to controls. Collectively, our results suggest that, in a model of type 1 diabetes, AGE accumulation primarily impairs SR Ca2+ reuptake in cardiac myocytes and that long-term treatment with an AGE cross-link breaker partially normalized SR Ca2+ handling and improved diabetic cardiomyopathy.
Highlights
Diabetes has become an epidemic disease and it is estimated that by the year 2025, it will affect over 300 million people worldwide (Amos et al, 1997; Boudina and Abel, 2007)
Treatment with an advanced glycation end products (AGEs) cross-link breaker, ALT-711, for 8 weeks did not significantly alter blood glucose concentration compared with untreated diabetic rats
In vivo VENTRICULAR FUNCTION We evaluated the effect of diabetes and ALT-711 therapy on systolic and diastolic function by echocardiographic examination in diabetic and control groups
Summary
Diabetes has become an epidemic disease and it is estimated that by the year 2025, it will affect over 300 million people worldwide (Amos et al, 1997; Boudina and Abel, 2007). Type 1 diabetes is characterized by sustained hyperglycemia resulting from the loss of insulinproducing pancreatic beta cells. This loss in insulin production results in dysfunctional glucose uptake in insulin-sensitive tissues (e.g., striated muscle) and causes multiple-organ complications. Within the past 30 years, diabetic cardiomyopathy has been identified as its own clinical unit, independent of coronary artery disease and atherosclerosis (Fang et al, 2004; Poornima et al, 2006). Because intracellular calcium (Ca2+) homeostasis is crucial for excitation-contraction coupling, chronic diabetes mellitus has been associated with impaired cardiac contractility and relaxation of the myocardium due to altered Ca2+ homeostasis
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