Chronic heart failure is a common complication in patients with type 2 diabetes mellitus (T2DM). T2DM is associated with disturbed metabolism of fat, which can result in excessive accumulation of lipids in cardiac muscle. In the current study, we assessed mitochondrial oxidation of carbohydrates and fatty acids, lipid accumulation, endoplasmic reticulum (ER) stress, and apoptosis in diabetic left ventricle. Left ventricular myocardium from 37 patients (a group of patients with diabetes and a group of patients without diabetes [ejection fraction >50%]) undergoing coronary artery bypass graft surgery was obtained by subepicardial needle biopsy. The group with diabetes had a significantly decreased rate of mitochondrial respiration fueled by palmitoyl-carnitine that correlated with blood glucose dysregulation, while there was no difference in oxidation of pyruvate. Diabetic myocardium also had significantly decreased activity of hydroxyacyl-CoA dehydrogenase (HADHA) and accumulated more lipid droplets and ceramide. Also, markers of ER stress response (GRP78 and CHOP) and apoptosis (cleaved caspase-3) were elevated in diabetic myocardium. These results show that, even in the absence of contractile failure, diabetic heart exhibits a decreased mitochondrial capacity for β-oxidation, increased accumulation of intracellular lipids, ER stress, and greater degree of apoptosis. Lower efficiency of mitochondrial fatty acid oxidation may represent a potential target in combating negative effects of diabetes on the heart.

The heart during myocardial stress, we hypothesized that such a mechanism is responsible for some of the cardiac benefits induced by exercise in postinfarction chronic heart failure (CHF). Methods Left ventricular myocytes were isolated from three groups of rats: Sham, CHF Tr (4 wk after myocardial infarction, rats underwent 8 wk of aerobic interval training 5 d·wk−1) and CHF Sed (rats sedentary for 12 wk after infarction). Cardiomyocyte survival after oxidative stress exposure (200 μM H2O2) and calcium handling (cells loaded with Fura-2 AM and electrically paced at 1 Hz) were assessed in the presence of KATP channel inhibitor glibenclamide. Expression of KATP subunits (SUR2A and Kir6.2) was evaluated using immunoblotting. Results Exercise improved cardiac function in CHF Tr animals. Cardiomyocytes from CHF Sed rats were more susceptible to oxidative stress-induced cell death than CHF Tr and Sham cardiomyocytes, with glibenclamide completely abolishing the protective effect of exercise. Glibenclamide did not affect cardiomyocyte survival in Sham or CHF Sed rats. In addition, exercise increased the systolic Ca2+ transient amplitude and improved diastolic Ca2+ removal in CHF Tr cardiomyocytes (compared with CHF Sed); both were significantly attenuated by glibenclamide. Exercise resulted in increased expression of KATP channel subunits in CHF Tr hearts, with more pronounced and significant effect on SUR2A. Conclusions Our data suggest that KATP channel upregulation induced by chronic exercise likely mediates some of exercise-induced beneficial effects on cardiac function in postischemic heart failure....

Chronic inflammation plays a role in all stages of atherosclerosis leading to coronary artery disease (CAD), with elevated inflammatory markers being associated with the worse clinical outcome. The goal of the current study was to examine possible association between pro-inflammatory/pro-coagulant factors; anticardiolipin (aCL) autoantibodies, complement C3, C4 and leptin, and the severity of CAD expressed as SYNTAX score. Patients with symptoms of cardiac ischemia undergoing coronary angiography were recruited, and their blood levels of aCL-IgG, aCL-IgM, complement C3, C4 and leptin were assessed. Their association with the SYNTAX score, calculated based on coronary angiography findings, was analyzed. All patients had aCL antibody titer within the normal range. A significant positive association was found for aCL-IgG and SYNTAX score. Male patients had higher average aCL-IgG concentration and SYNTAX score than female patients. No association was found between SYNTAX score and C3 and C4. On the other hand, leptin was negatively associated with SYNTAX score. Our study demonstrates an association between the extent of CAD and aCL-IgG even in the absence of systemic autoimmune disease and at the aCL-IgG levels that are within the normal range. Also, association of lower leptin levels with more severe CAD suggests that its pro-inflammatory effects might not contribute to the pathogenesis of CAD, and that leptin might even exert protective effects on coronary vasculature.

Numerous studies reported about potential effects of L-carnosine in regulation of tumor growth and metabolism. We evaluated the effects of different concentrations of L-carnosine from Karnozin EXTRA (R) supplement on mitochondrial respiratory chain complexes of human embryo lung fibroblasts (MRC-5) and human breast cancer cells (MCF-7), with different energy pathways. Also, we analyzed the proliferation index and expression of various markers of oxidative stress. Treatment with Karnozin EXTRA (R) (concentration of L-carnosine were 2, 5 and 10 mM) for 24 hours gradually decreased the number of cells and changed their morphological features. In both cell lines, a dose-dependent reduction of cell viability was recorded compared to the control group. Also, experimental groups showed a concentration-dependent decrease in fluorescence intensity of SOD2 expressions in MCF-7, while in MRC-5 we noticed higher fluorescence intensity in Carnosine 2 mM group. Treated cells, in both cell lines, showed different intensity of iNOS cytoplasmic immunopositivity in a concentration-dependent manner. In all experimental groups, we noticed an increased expression of marker of oxidative stress-cytochrome P450 2E1 (CYP2E1). The effects of Karnozin EXTRA (R) capsule on mitochondrial respiration, assessed with the Clark-type electrode, were manifested as a reduction of: basal cell respiration, maximum capacity of electron transport chain and mitochondrial ATP-linked respiration. Also, significant decrease in the activity of complex I (NADH-ubiquinone oxidoreductase), complex II (succinate dehydrogenase) and complex IV (cytochrome c oxidase) was observed in both cell lines. Bearing in mind that Karnozin EXTRA (R) is a potential regulator of energy metabolism of MCF-7 and MRC-5, these results provide a good basis for further preclinical and clinical research.

Mitochondrial reactive oxygen species (ROS) play a central role in cardiac ischemia/reperfusion injury, heart failure, and arrhythmogenesis, while also serving essential signaling functions under physiological conditions. Among the eleven identified mitochondrial ROS-producing sites, complexes I and III are considered the major contributors, particularly under conditions of impaired electron flow. However, much of the existing knowledge comes from rodent models or cultured cells and is often assumed to apply to humans. Here, ROS production from complexes I and III was measured directly in human myocardial and skeletal muscle biopsies and compared with corresponding rat tissues under identical experimental conditions. Hydrogen peroxide generation was quantified using Amplex UltraRed, with simultaneous monitoring of mitochondrial respiration using a Clark-type oxygen electrode. Across all examined mechanisms—reverse and forward electron transport at complex I and the ubiquinol oxidation site of complex III, rat tissues produced more ROS than human tissues, consistent with their higher respiratory rates. However, the dominant ROS-producing sites differed: in rats, complex III was the primary source, whereas in human tissues the highest ROS production occurred during reverse electron transport at complex I. When normalized to respiration, human tissues showed relatively greater ROS generation at complex I but markedly lower production at complex III. These direct measurements of mitochondrial ROS production in human myocardium provide new insight into cardiac redox physiology and may explain the limited clinical translation of cardioprotective strategies targeting mitochondrial ROS production, such as interventions aimed at modulating reperfusion injury or preconditioning.