Significance: Diabetic cardiomyopathy (DCM) is a frequent complication occurring even in well-controlled asymptomatic diabetic patients, and it may advance to heart failure (HF). Recent Advances: The diabetic heart is characterized by a state of “metabolic rigidity” involving enhanced rates of fatty acid uptake and mitochondrial oxidation as the predominant energy source, and it exhibits mitochondrial electron transport chain defects. These alterations promote redox state changes evidenced by a decreased NAD ⁺ /NADH ratio associated with an increase in acetyl-CoA/CoA ratio. NAD ⁺ is a co-substrate for deacetylases, sirtuins, and a critical molecule in metabolism and redox signaling; whereas acetyl-CoA promotes protein lysine acetylation, affecting mitochondrial integrity and causing epigenetic changes. Critical Issues: DCM lacks specific therapies with treatment only in later disease stages using standard, palliative HF interventions. Traditional therapy targeting neurohormonal signaling and hemodynamics failed to improve mortality rates. Though mitochondrial redox state changes occur in the heart with obesity and diabetes, how the mitochondrial NAD ⁺ /NADH redox couple connects the remodeled energy metabolism with mitochondrial and cytosolic antioxidant defense and nuclear epigenetic changes remains to be determined. Mitochondrial therapies targeting the mitochondrial NAD ⁺ /NADH redox ratio may alleviate cardiac dysfunction. Future Directions: Specific therapies must be supported by an optimal understanding of changes in mitochondrial redox state and how it influences other cellular compartments; this field has begun to surface as a therapeutic target for the diabetic heart. We propose an approach based on an alternate mitochondrial electron transport that normalizes the mitochondrial redox state and improves cardiac function in diabetes.

Ischaemia/reperfusion (I/R) injury of the heart represents a major health burden mainly associated with acute coronary syndromes. While timely coronary reperfusion has become the established routine therapy in patients with ST‐elevation myocardial infarction, the restoration of blood flow into the previously ischaemic area is always accompanied by myocardial injury. The central mechanism involved in this phenomenon is represented by the excessive generation of reactive oxygen species (ROS). Besides their harmful role when highly generated during early reperfusion, minimal ROS formation during ischaemia and/or at reperfusion is critical for the redox signaling of cardioprotection. In the past decades, mitochondria have emerged as the major source of ROS as well as a critical target for cardioprotective strategies at reperfusion. Mitochondria dysfunction associated with I/R myocardial injury is further described and ultimately analyzed with respect to its role as source of both deleterious and beneficial ROS. Furthermore, the contribution of ROS in the highly investigated field of conditioning strategies is analyzed. In the end, the vascular sources of mitochondria‐derived ROS are briefly reviewed.

Introduction: Ischemia/reperfusion (I/R) injury, such as myocardial infarction, stroke, and peripheral vascular disease, has been recognized as the most frequent causes of devastating disorders and death currently. Protective effect of various preconditioning stimuli, including hyperbaric oxygen (HBO), has been proposed in the management of I/R.Methods: In this study, we searched and reviewed up‐to‐date published papers to explore the pathophysiology of I/R injury and to understand the mechanisms underlying the protective effect of HBO as conditioning strategy.Results: Animal study and clinic observation support the notion that HBO therapy and conditioning provide beneficial effect against the deleterious effects of postischemic reperfusion. Several explanations have been proposed. The first likely mechanism may be that HBO counteracts hypoxia and reduces I/R injury by improving oxygen delivery to an area with diminished blood flow. Secondly, by reducing hypoxia–ischemia, HBO reduces all the pathological events as a consequence of hypoxia, including tissue edema, increased affective area permeability, postischemia derangement of tissue metabolism, and inflammation. Thirdly, HBO may directly affect cell apoptosis, signal transduction, and gene expression in those that are sensitive to oxygen or hypoxia. HBO provides a reservoir of oxygen at cellular level not only carried by blood, but also by diffusion from the interstitial tissue where it reaches high concentration that may last for several hours, improves endothelial function and rheology, and decreases local inflammation and edema.Conclusion: Evidence suggests the benefits of HBO when used as a preconditioning stimulus in the setting of I/R injury. Translating the beneficial effects of HBO into current practice requires, as for the “conditioning strategies”, a thorough consideration of risk factors, comorbidities, and comedications that could interfere with HBO‐related protection.

Monoamine oxidases (MAOs) generate H ₂ O ₂ as a by-product of their catalytic cycle. Whether MAOs are mediators of endothelial dysfunction is unknown and was determined here in the angiotensin II and lipopolysaccharide-models of vascular dysfunction in mice. Quantitative real-time polymerase chain reaction revealed that mouse aortas contain enzymes involved in catecholamine generation and MAO-A and MAO-B mRNA. MAO-A and -B proteins could be detected by Western blot not only in mouse aortas but also in human umbilical vein endothelial cells. Ex vivo incubation of mouse aorta with recombinant MAO-A increased H ₂ O ₂ formation and induced endothelial dysfunction that was attenuated by polyethylene glycol-catalase and MAO inhibitors. In vivo lipopolysaccharide (8 mg/kg IP overnight) or angiotensin II (1 mg/kg per day, 2 weeks, minipump) treatment induced vascular MAO-A and -B expressions and resulted in attenuated endothelium-dependent relaxation of the aorta in response to acetylcholine. MAO inhibitors reduced the lipopolysaccharide- and angiotensin II–induced aortic reactive oxygen species formation by 50% (ferrous oxidation xylenol orange assay) and partially normalized endothelium-dependent relaxation. MAO-A and MAO-B inhibitors had an additive effect; combined application completely restored endothelium-dependent relaxation. To determine how MAO-dependent H ₂ O ₂ formation induces endothelial dysfunction, cyclic GMP was measured. Histamine stimulation of human umbilical vein endothelial cells to activate endothelial NO synthase resulted in an increase in cyclic GMP, which was almost abrogated by MAO-A exposure. MAO inhibition prevented this effect, suggesting that MAO-induced H ₂ O ₂ formation is sufficient to attenuate endothelial NO release. Thus, MAO-A and MAO-B are both expressed in the mouse aorta, induced by in vivo lipopolysaccharide and angiotensin II treatment and contribute via the generation of H ₂ O ₂ to endothelial dysfunction in vascular disease models.

Background: Recent investigations have focused on the pivotal role of the mitochondria in the underlying mechanisms volatile anesthetic-induced myocardial preconditioning. This study aimed at examining the effect of anesthetic preconditioning on mitochondrial permeability transition (MPT) pore opening. Methods: Anesthetized open chest rabbits were randomized to one of four groups and underwent 10 min of ischemia, except for the sham 1 group (n = 12). Before this, they underwent a treatment period consisting of (1) no intervention (ischemic group; n = 12), (2) 30 min of desflurane inhalation (8.9% end-tidal concentration) followed by a 15-min washout period (desflurane group; n = 12), or (3) ischemic preconditioning (IPC group; n = 12). A second set of experiments was performed to evaluate the effect of a putative mitochondrial adenosine triphosphate-sensitive potassium channel antagonist, 5-hydroxydecanoate (5-HD). The animals underwent the same protocol as previously, plus pretreatment with 5 mg/kg 5-HD. They were randomized to one of five groups: the sham 2 group, receiving no 5-HD (n = 12); the sham 5-HD group (n = 12); the ischemic 5-HD group (n = 12), the desflurane 5-HD group (n = 12), and the IPC 5-HD group (n = 12). At the end of the protocol, the hearts were excised, and mitochondria were isolated. MPT pore opening was assessed by measuring the amount of calcium required to trigger a massive calcium release indicative of MPT pore opening. Results: Desflurane and IPC group mitochondria needed a higher calcium load than ischemic group mitochondria (362 +/- 84, 372 +/- 74, and 268 +/- 110 microM calcium, respectively; P < 0.05) to induce MPT pore opening. The sham 1 and sham 2 groups needed a similar amount of calcium to trigger mitochondrial calcium release (472 +/- 70 and 458 +/- 90 microM calcium, respectively). 5-HD preadministration had no effect on sham animals (458 +/- 90 and 440 +/- 128 microM calcium without and with 5-HD, respectively) and ischemic group animals (268 +/- 110 and 292 +/- 102 microM calcium without and with 5-HD, respectively) but abolished the effects of desflurane on calcium-induced MPT pore opening (362 +/- 84 microM calcium without 5-HD vs. 238 +/- 96 microM calcium with 5-HD; P < 0.05) and IPC (372 +/- 74 microM calcium without 5-HD vs. 270 +/- 104 microM calcium with 5-HD; P < 0.05). Conclusion: Like ischemic preconditioning, desflurane improved the resistance of the transition pore to calcium-induced opening. This effect was inhibited by 5-HD, suggesting a link between mitochondrial adenosine triphosphate-sensitive potassium and MPT.

Betulinic acid (BA), a natural compound with a lupan skeleton, has been highly investigated in the past decade for a plethora of beneficial properties, including anti-cancer, anti-inflammatory, anti-angiogenic, immune-modulatory, and anti-HIV effects. In particular, BA has been reported to be effective in vitro against tumor cell lines of different origins, and also in vivo, in animal models of cancer. The best characterized mechanism of its antitumor effect consists of triggering apoptosis via the mitochondrial pathway. BA has also an anti-metastatic effect via the prevention of the epithelial-to-mesencymal transition in highly aggressive melanoma cells. Furthermore, in the same model, BA is able to counteract the pro-invasive potential of the pro-tumoral protein neutrophil gelatinaseassociated lipocalin. The present review addresses the current state of knowledge regarding the anti-tumor effects of betulinic acid, a potent chemotherapeutic agent.