Neuronal intracellular Ca 2+ homeostasis is critical to the normal physiological functions of neurons and neuronal Ca 2+ dyshomeostasis has been associated with the age-related decline of cognitive functions. Accumulated evidence indicates that the underlying mechanism for this is that abnormal intracellular Ca 2+ levels stimulate the dysregulation of intracellular signaling, which subsequently induces neuronal cell death. We examined intracellular Ca 2+ homeostasis in cortical (in vivo) and hippocampal (in vitro) neurons from young (3-months), middle-age (12-months), and aged (24-months) wild type C57BL6J mice. We found a progressive age-related elevation of intracellular resting calcium ([Ca 2+ ] r) in cortical (in vivo) and hippocampal (in vitro) neurons associated with increased hippocampal neuronal calpain activity and reduced cell viability. In vitro, removal of extracellular Ca 2+ or treatment with SAR7334 or dantrolene reduced [Ca 2+ ] r in all age groups and dantrolene treatment lowered calpain activity and increased cell viability. In vivo, both middle-aged and aged mice showed cognitive deficits compared to young mice, which improved after dantrolene treatment. These findings support the hypothesis that intracellular Ca 2+ dyshomeostasis is a major mechanism underlying the cognitive deficits seen in both normal aging and degenerative neurologic diseases.
Diabetic cardiomyopathy (DCM) is a primary disease in diabetic patients characterized by diastolic dysfunction leading to heart failure and death. Unfortunately, even tight glycemic control has not been effective in its prevention. We have found aberrant diastolic Ca2+ concentrations ([Ca2+]d), decreased glucose transport, elevated production of reactive oxygen species (ROS), and increased calpain activity in cardiomyocytes from a murine model (db/db) of type 2 diabetes (T2D). Cardiomyocytes from these mice demonstrate significant cell injury, increased levels of tumor necrosis factor-alpha and interleukin-6 and expression of the transcription nuclear factor-κB (NF-κB). Furthermore, decreased cell viability, and reduced expression of Kir6.2, SUR1, and SUR2 subunits of the ATP-sensitive potassium (KATP) channels. Treatment of T2D mice with the citrus fruit flavonoid naringin for 4 weeks protected cardiomyocytes by reducing diastolic Ca2+ overload, improving glucose transport, lowering reactive oxygen species production, and suppressed myocardial inflammation. In addition, naringin reduced calpain activity, decreased cardiac injury, increased cell viability, and restored the protein expression of Kir6.2, SUR1, and SUR2 subunits of the KATP channels. Administration of the KATP channel inhibitor glibenclamide caused a further increase in [Ca2+]d in T2D cardiomyocytes and abolished the naringin effect on [Ca2+]d. Nicorandil, a KATP channel opener, and nitric oxide donor drug mimic the naringin effect on [Ca2+]d in T2D cardiomyocyte; however, it aggravated the hyperglycemia in T2D mice. These data add new insights into the mechanisms underlying the beneficial effects of naringin in T2D cardiomyopathy, thus suggesting a novel approach to treating this cardiovascular complication.
Background: Diabetes mellitus (DM) is a major risk factor for the development of cardiovascular disease. Over time, diabetic patients develop cardiomyopathy, referred to as diabetic cardiomyopathy (DCM). The etiology of DCM in part relates to the duration of hyperglycemia. We have previously shown that type 1 diabetic mice (T1D) have abnormally elevated cardiomyocyte diastolic [Ca 2+ ] d , sodium ([Na + ] d ) after 3 months of diabetes. Whole body periodic acceleration (WBPA) is the motion of the supine body headward to footward in a sinusoidal fashion to induce pulsatile shear stress, increasing expression and phosphorylation of endothelial-derived nitric oxide synthase (eNOS, p-eNOS). We have previously shown that WBPA decreases [Ca 2+ ] d , sodium ([Na + ] d in various models of cardiomyopathy. We hypothesized that WBPA might reverse ion dyshomeostasis in the long term (15-months) hyperglycemia (glucose>250mg/dl) mice. Methods: 15 C57BL/6J (CONT) and diabetic mice (T1D) were randomized to receive WBPA (480 rpm, 1 hr daily for 20 days). Diastolic [Ca 2+ ] d , ([Na + ] d ) (selective microelectrodes), and ROS production (fluorescent) were determined in isolated cardiomyocytes at day 0 and at upon completion of the treatment (day 20). Results: Hyperglycemia produced an increase in [Ca 2+ ] d , [Na + ] d and ROS production in cardiomyocytes. 20 days of WBPA treatment in established DCM significantly decreased [Ca 2+ ] d , [Na + ] d , and ROS production toward normal values. Conclusions: These findings suggest that WBPA may be a therapeutic strategy to reverse ion dyshomeostasis and oxidative stress in a very established(15mos) DCM
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