Role Of Calcium-sensing Receptors Activation In Diabetic Cardiac Injury

Cardiac injury is a common pathological change accompanying diabetes mellitus.Recently, some evidence indicated that calcium-sensing receptor （CaSR） expressed inthe cardiac tissue. However, the functional role of CaSR in diabetic cardiac injuryremains unclear. The present study was designed to investigate the relationshipbetween CaSR activation and diabetes-induced cardiac injury. Apoptotic rate wasmeasured by TUNEL staining and flow cytometry. The expression of Bcl-2, Bax,extracellular signal-regulated protein kinase （ERK）, c-Jun NH2-terminal proteinkinase （JNK） and p38were examine by western blot, and the intracellular calciumconcentration ([Ca²⁺]i) was detected by laser scanning confocal microscopy. Diabeticmodel was successfully established by administration with streptozotocin （STZ） invivo, and cardiomyocytes injury was simulated by25.5mmol/L glucose in vitro. Wedemonstrated that there existed significant increase in left ventricular end-diastolicpressure （LVEDP） as well as decrease in maximum rate of left ventricular pressurerise and fall （±dp/dtmax） and left ventricular systolic pressure （LVSP）, and alsoobserved cardiomyocytes apoptosis by TUNEL staining. In vitro,25.5mmol/Lglucose could induce rat neonatal ventricular cardiomyocytes apoptosis detected byflow cytometry. Further results showed that treatment with25.5mmol/L glucosesignificantly increased [Ca²⁺]i, up-regulated the expression of Bax, P-ERK and P-JNK,and suppressed the expression of Bcl-2. However, the above deleterious changes werefurther obvious when co-treatment with CaSR agonist GdCl₃（300μmol/L）. But theeffects of GdCl₃were attenuated by200nmol/L NPS-2390, a specific inhibitor ofCaSR. In conclusion, these results suggest that CaSR activation could lead to theapoptosis of cardiomyocytes in diabetic cardiac injury through the induction ofcalcium overload and the activation of the mitochondrial and mitogen-activated protein kinase pathway. These findings may serve as potential therapeutic and drugtargets.