Abstract
Background Metabolic alterations as hyperglycemia and inflammation induce myocardial molecular events enhancing oxidative stress and mitochondrial dysfunction. Those alterations are responsible for a progressive loss of cardiomyocytes, cardiac stem cells, and consequent cardiovascular complications. Currently, there are no effective pharmacological measures to protect the heart from these metabolic modifications, and the development of new therapeutic approaches, focused on improvement of the oxidative stress condition, is pivotal. The protective effects of levocarnitine (LC) in patients with ischemic heart disease are related to the attenuation of oxidative stress, but LC mechanisms have yet to be fully understood. Objective The aim of this work was to investigate LC's role in oxidative stress condition, on ROS production and mitochondrial detoxifying function in H9c2 rat cardiomyocytes during hyperglycemia. Methods H9c2 cells in the hyperglycemic state (25 mmol/L glucose) were exposed to 0.5 or 5 mM LC for 48 and 72 h: LC effects on signaling pathways involved in oxidative stress condition were studied by Western blot and immunofluorescence analysis. To evaluate ROS production, H9c2 cells were exposed to H2O2 after LC pretreatment. Results Our in vitro study indicates how LC supplementation might protect cardiomyocytes from oxidative stress-related damage, preventing ROS formation and activating antioxidant signaling pathways in hyperglycemic conditions. In particular, LC promotes STAT3 activation and significantly increases the expression of antioxidant protein SOD2. Hyperglycemic cardiac cells are characterized by impairment in mitochondrial dysfunction and the CaMKII signal: LC promotes CaMKII expression and activation and enhancement of AMPK protein synthesis. Our results suggest that LC might ameliorate metabolic aspects of hyperglycemic cardiac cells. Finally, LC doses herein used did not modify H9c2 growth rate and viability. Conclusions Our novel study demonstrates that LC improves the microenvironment damaged by oxidative stress (induced by hyperglycemia), thus proposing this nutraceutical compound as an adjuvant in diabetic cardiac regenerative medicine.
Highlights
Cardiovascular complications are recognized as the primary cause of mortality in subjects with diabetes mellitus (DM) [1, 2], characterized by hyperglycemia which is determined by a defect of insulin secretion, insulin action, or both [3]
DAPI images showed that pretreated H9c2 cells with LC, in particular with 5 mM LC, showed a higher number of nuclei than the control condition (Figures 2(b) and 2(d)): These results suggested that LC pretreatment improved cellular survival after H2O2 injury
We demonstrated that LC supplementation significantly decreases reactive oxygen species (ROS) production in cardiomyocytes during hyperglycemia (Figure 2)
Summary
Cardiovascular complications are recognized as the primary cause of mortality in subjects with diabetes mellitus (DM) [1, 2], characterized by hyperglycemia which is determined by a defect of insulin secretion, insulin action, or both [3]. Balestrieri et al demonstrated that SIRT6 protein expression is downregulated in atherosclerotic plaques of diabetics, and this defect is linked to the chronic oxidative stress condition [6]. Metabolic alterations as hyperglycemia and inflammation induce myocardial molecular events enhancing oxidative stress and mitochondrial dysfunction. Those alterations are responsible for a progressive loss of cardiomyocytes, cardiac stem cells, and consequent cardiovascular complications. Hyperglycemic cardiac cells are characterized by impairment in mitochondrial dysfunction and the CaMKII signal: LC promotes CaMKII expression and activation and enhancement of AMPK protein synthesis. Our novel study demonstrates that LC improves the microenvironment damaged by oxidative stress (induced by hyperglycemia), proposing this nutraceutical compound as an adjuvant in diabetic cardiac regenerative medicine
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