Diabetes and cardiovascular disease: the road to cardioprotection.
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Animals↗
Biomedical subjects
Lino Gonçalves
Publications and source records attributed to Lino Gonçalves.
Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria?
The cellular role of mitochondria includes ATP generation and the modulation of cytosolic calcium signals, besides being the "crossroads" for several cell death pathways. The maintenance of optimal mitochondrial functioning during the disease process increases the chances for survival. For example, ischaemia followed by reperfusion is known to negatively affect mitochondrial function, namely by inducing a deleterious condition called mitochondrial permeability transition (MPT). The MPT is responsible for mitochondrial dysfunction and can ultimately lead to cell death. Therefore, it seems important to protect mitochondrial function in cardiac disease. Carvedilol, a beta-adrenergic receptor antagonist with antioxidant properties, has a positive impact on cardiac mitochondria during in vitro, ex-vivo and in vivo models of cardiac dysfunction. Particularly, carvedilol was shown to inhibit MPT in isolated heart mitochondria and protect mitochondria against the oxidative damage induced by the xanthine oxidase/hypoxanthine pro-oxidant system. The observation that carvedilol acts as an inhibitor of mitochondrial complex-I is also of importance, since this mitochondrial system was proposed as cause of the cardiotoxicity associated with the anti-neoplasic drug doxorubicin. This review points out the major findings concerning the positive impact of carvedilol on mitochondrial function and its use in the treatment of myocardial diseases where oxidative stress is known to be involved.
Adrenergic beta-Antagonists↗
Lupus myocarditis. Case report.
Myocarditis is one of the many possible forms of cardiac involvement in systemic lupus erythematosus. Its clinical presentation ranges from asymptomatic patients with self-limited disease to fulminant heart failure that can lead to death. In most cases treatment consists of supportive care only. The authors present the case of a patient with lupus myocarditis.
Adolescent↗
Advantages in the use of carvedilol versus propranolol for the protection of cardiac mitochondrial function.
BACKGROUND: Carvedilol is a neurohormonal antagonist of multiple action which is used in clinical practice for the treatment of congestive heart failure, mild to moderate hypertension and myocardial infarction. Previous results from our group have demonstrated that one of the main targets for the protective effect of carvedilol is the cardiac mitochondrial network. In-this work, we compare the effect of carvedilol with propranolol in different models of mitochondrial dysfunction and in the generation of transmembrane electric potential (EP). We further tested if carvedilol was able to inhibit the mitochondrial permeability transition (MPT) induced by doxorubicin and calcium-dependent cytochrome c release, a phenomenon frequently associated with apoptotic cell death. METHODS: Cardiac mitochondria were isolated by differential centrifugation. Oxygen consumption and mitochondrial EP were determined using an oxygen electrode and a tetraphenylphosphonium-sensitive electrode, respectively. Changes in mitochondrial volume and the release of cytochrome c were measured with spectrophotometric techniques. RESULTS: Propranolol, compared with carvedilol, had only a marginal effect, not only in protection against MPT induction, but also against oxygen consumption linked to the oxidation of external NADH, a process that is considered by several authors as key in the cardiotoxicity of doxorubicin. Regarding EP generation, propranolol had no effect, in contrast to carvedilol, which was confirmed to act as a protonophore. For the first time we also show that carvedilol inhibits the MPT induced by doxorubicin and calcium-dependent cytochrome c release. CONCLUSIONS: With this work, we further support the notion that carvedilol is effective in several models of mitochondrial dysfunction, particularly those involving oxidative stress. The results demonstrate that for some pathological conditions, carvedilol and propranolol have different mechanisms of action at the sub-cellular level, as propranolol seems to lack effectiveness in the protection of cardiac mitochondria.
Animals↗
Carvedilol: relation between antioxidant activity and inhibition of the mitochondrial permeability transition.
OBJECTIVES: The mitochondrial permeability transition (MPT) is an event related to severe oxidative stress (for example, during myocardial ischemia and reperfusion) and excessive mitochondrial calcium accumulation, also being implicated in cell death. In this study, we compared the effect of carvedilol on the cardiac MPT induced by calcium and phosphate (Ca/Pi) and calcium/carboxyatractyloside (Ca/Catr). Oxidative stress plays a major role in MPT induction by Ca/Pi, leading to the oxidation of protein thiol groups, in contrast with Ca/Catr, where such oxidation is secondary to MPT induction and is not caused by oxidative stress. MATERIALS AND METHODS: Mitochondria were isolated from rat hearts and parameters related to MPT induction were evaluated (n = 5 for each inducer): mitochondrial swelling and oxidation of protein thiol groups (both measured by spectrophotometry). RESULTS: Using Ca/Pi, carvedilol protected mitochondria from MPT induction, particularly in its high conductance form. Its effect was demonstrated by analyzing the decrease in mitochondrial swelling amplitude. Simultaneously, we observed inhibition of protein thiol group oxidation (p < 0.001). By contrast, carvedilol did not show any protective effect with Ca/Catr. CONCLUSIONS: Carvedilol was only effective against the MPT when the oxidation of protein thiol groups was the cause and not the consequence of the MPT phenomenon. The results clearly show that during myocardial aggressions (ischemia and reperfusion, for example), the protective effect of carvedilol is primarily due to an antioxidant mechanism, inhibiting the production and effects of reactive oxygen species.
Animals↗
Pyruvate improves mitochondrial bioenergetics in an ex-vivo animal model of myocardial ischemia.
Pyruvate is an energy substrate with known cardioprotective activity. We know now that this is due not only to its antioxidant activity, but also to its reduction of intracellular acidosis, modulation of intracytosolic calcium and improvement of cardiomyocyte contractility. However, the role of cardiac mitochondria in such positive effects has only recently begun to be understood and the exact mechanisms of the effect of pyruvate on mitochondria are still largely unknown. Aiming to study the effect of pyruvate on cardiac mitochondrial function during acute ischemia, we used an ex-vivo animal model, perfused in a Langendorff system and then subjected to ischemia in the presence and absence of pyruvate. We evaluated the mitochondrial membrane electrical potential, the respiratory chain O2 consumption (and respiratory control ratio) and the energy charges generated with different energy substrates. We conclude that pyruvate has some effect on the mitochondrial oxidative system (by non-significantly improving the respiratory control ratio), but its main action is on the phosphorylation system, significantly decreasing the time taken to complete a phosphorylation cycle (lag phase) and improving ATP production (increase in energy charge), thus allowing better maintenance of mitochondrial membrane structure, with consequent improvement of the electrical potential after a phosphorylation cycle. These findings have enabled better understanding of the mechanisms behind pyruvate cytoprotection in ischemic cardiomyopathy, clearly highlighting the essential role of cardiac mitochondria in this process.
Animals↗
Mitochondria: role in ischemia, reperfusion and cell death.
Recent advances in the knowledge of the biochemical basis of myocardial ischemia have enabled a better understanding of the complex sequence of events occurring in ischemic cardiomyopathy, whatever its manifestations. This has clearly highlighted the important role played by cardiac mitochondria in these events. At first only associated with energy production, mitochondria have been clearly shown to have other important functions, like the maintenance of calcium homeostasis, as well as ischemic and non-ischemic preconditioning, and also modulation of cellular life and death. The aims of this review are twofold: firstly, to review the current knowledge on mitochondrial morphology and structure, and how these can be affected by ischemia and ischemia-reperfusion; and secondly, to summarize the role of cardiac mitochondria in cardioprotection and modulation of cell death mechanisms.
Cell Death↗
Impact of diabetes on induction of the mitochondrial permeability transition.
Diabetes is one of the most common metabolic diseases of our times. Specific cardiovascular alterations are often associated with the progression of this disease. Considerable controversy exists in the literature concerning the greater or lesser susceptibility of the diabetic heart to ischemia and reperfusion. Cardiac mitochondria may be fundamental to the differential susceptibility of the cardiomyocyte to pathologic phenomena, particularly those due to the induction of the degenerative process known as the mitochondrial permeability transition (MPT), which is triggered by excessive mitochondrial calcium accumulation. The MPT has been associated with cellular dysfunction resulting from ischemia and reperfusion. The objective of this work was to examine the susceptibility of mitochondria isolated from diabetic rats to the MPT, in comparison to healthy control rats of the same age. Cardiac mitochondria from the diabetic rats had higher calcium loading capacity before the development of the MPT, with a decreased incidence of MPTP-associated features. This was associated with a greater capacity to sustain multiple pulses of externally added calcium, simultaneously with maintenance of the transmembrane electrical potential and reduced swelling amplitude. This could mean that cardiomyocytes from diabetic hearts may indeed be less prone to dysfunctions resulting from ischemia and reperfusion, at least in milder diabetic conditions, thus explaining many reports in the literature.
Animals↗
Impact of carvedilol on the mitochondrial damage induced by hypoxanthine and xantine oxidase--what role in myocardial ischemia and reperfusion?
OBJECTIVES: The cardioprotective effects of carvedilol (CV) may be explained in part by interactions with heart mitochondria. The objective of this work was to study the protection afforded by CV against oxidative stress induced in isolated heart mitochondria by hypoxanthine and xanthine oxidase (HX/XO), a well-known source of reactive oxygen species (ROS) in the cardiovascular system. METHODS: Mitochondria were isolated from Wistar rat hearts (n = 8) and incubated with HX/XO in the presence and in the absence of calcium. Several methods were used to assess the protection afforded by CV: evaluation of mitochondrial volume changes (by measuring changes in the optical density of the mitochondrial suspension), calcium uptake and release (with a fluorescent probe, Calcium Green 5-N) and mitochondrial respiration (with a Clark-type oxygen electrode). RESULTS: CV decreased mitochondrial damage associated with ROS production by HX and XO, as verified by the reduction of mitochondrial swelling and increase in mitochondrial calcium uptake. In the presence of HX and XO, CV also ameliorated mitochondrial respiration in the active phosphorylation state and prevented decrease in the respiratory control ratio (p < 0.05) and in mitochondrial phosphorylative efficiency (p < 0.001). CONCLUSIONS: The data indicate that CV partly protected heart mitochondria from oxidative damage induced by HX and XO, which may be useful during myocardial ischemia and reperfusion. It is also suggested that mitochondria may be a priority target for the protective action of some compounds.
Animals↗