Perturbation of intracellular Ca2+ cycling is a primary cause for the depressed myocardial contractility in individuals with type 1 diabetes (T1D) and in all animal models of T1D. One of the proteins that contribute to this defect is type 2 ryanodine receptor (RyR2), the channel through which Ca2+ leave the sarcoplasmic reticulum to effect contraction. To date, precise molecular mechanisms responsible for RyR2 dysfunction during T1D remain unknown. Our laboratory recently found that dysfunctional RyR2 from streptozotocin (STZ)-induced diabetic rat hearts contain carbonyl adducts on select basic residues. Treatment of diabetic rats with pyridoxamine to scavenge reactive carbonyl species blunted diabetes-induced dysfunction of RyR2, normalize myocyte excitation-contraction coupling and myocardial contractility. Exercise training STZ-diabetic rats also reduced production of reactive carbonyl species, decreased formation of carbonyl adducts on RyR2, restored excitation-contract coupling in ventricular myocytes and blunted diabetes- induced reduction in myocardial contractility. These new data suggest that formation of carbonyl adducts (carbonylation) of long-lived RyR2 is functionally important and not an epiphenomenon of diabetes. Our central hypothesis is """"""""diabetes leads to carbonylation of critical amino acid residues on RyR2, causing RyR2 dysfunction, impairment of excitation-contraction coupling and heart failure."""""""" We will use cell culture and STZ-diabetic rat models to (i) elucidate molecular mechanisms by which carbonyl adducts alter RyR2 function during diabetes, and (ii) determine molecular mechanisms by which pyridoxamine treatment and exercise training attenuate RyR2 dysfunction during T1D. Data from this project will provide valuable mechanistic insights into how this group of understudied cellular oxidants (reactive carbonyl species) impairs the activity of RyR2, leading to defective excitation-contraction coupling and reduced myocardial contractility during T1D. Since carbonyl stress and carbonylation of proteins also occurs in type 2 diabetes and metabolic syndrome, knowledge gained from this project could also be useful in designing newer therapeutic strategies for management of myocardial dysfunction in these individuals as well. Lay summary: Heart failure is a primary cause of morbidity and mortality in diabetic patients. However, the cause of this heart failure is not fully understood. This project is designed to further our understanding as to why the heart fails in individuals with diabetes. This research is especially important since it could help in the development of newer therapeutic strategies/options to improve the quality of life of diabetic patients and control the escalating economic cost of diabetes care, which is estimated to be in excess of $132 billion annually.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Liang, Isabella Y
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University of Nebraska Medical Center
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Tian, Chengju; Alomar, Fadhel; Moore, Caronda J et al. (2014) Reactive carbonyl species and their roles in sarcoplasmic reticulum Ca2+ cycling defect in the diabetic heart. Heart Fail Rev 19:101-12
Tian, Chengju; Moore, Caronda J; Dodmane, Puttappa et al. (2013) Dust from hog confinement facilities impairs Ca2+ mobilization from sarco(endo)plasmic reticulum by inhibiting ryanodine receptors. J Appl Physiol (1985) 114:665-74
Moore, Caronda J; Shao, Chun Hong; Nagai, Ryoji et al. (2013) Malondialdehyde and 4-hydroxynonenal adducts are not formed on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) in diabetes. Mol Cell Biochem 376:121-35
Shao, Chun Hong; Tian, Chengju; Ouyang, Shouqiang et al. (2012) Carbonylation induces heterogeneity in cardiac ryanodine receptor function in diabetes mellitus. Mol Pharmacol 82:383-99
Tian, Chengju; Shao, Chun Hong; Moore, Caronda J et al. (2011) Gain of function of cardiac ryanodine receptor in a rat model of type 1 diabetes. Cardiovasc Res 91:300-9
Shao, Chun Hong; Capek, Haley L; Patel, Kaushik P et al. (2011) Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes. Diabetes 60:947-59
Tian, Chengju; Shao, Chun Hong; Fenster, Danielle S et al. (2010) Chloroform extract of hog barn dust modulates skeletal muscle ryanodine receptor calcium-release channel (RyR1). J Appl Physiol 109:830-9
Shao, Chun-Hong; Rozanski, George J; Nagai, Ryoji et al. (2010) Carbonylation of myosin heavy chains in rat heart during diabetes. Biochem Pharmacol 80:205-17
Shao, Chun-Hong; Wehrens, Xander H T; Wyatt, Todd A et al. (2009) Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation. J Appl Physiol (1985) 106:1280-92
Bidasee, Keshore R; Zheng, Hong; Shao, Chun-Hong et al. (2008) Exercise training initiated after the onset of diabetes preserves myocardial function: effects on expression of beta-adrenoceptors. J Appl Physiol 105:907-14

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