Mitochondria are the powerhouses of the living cell, producing most of the cell’s energy by oxida... more Mitochondria are the powerhouses of the living cell, producing most of the cell’s energy by oxidative phosphorylation. The process of energy transduction requires the coordinated action of 4 major respiratory enzyme complexes and ATP synthase (F 0 F 1 ATPase). High-resolution structures are now available for the bacterial complex I, complete structures of mammalian complexes II to IV, and F 1 ATPase (peripheral or headpiece domain of F 0 F 1 ATPase). In addition, the mitochondria play a central role in the regulation of programmed cell death. The mitochondria trigger apoptosis by impairing electron transport and energy metabolism, by releasing cytochrome c and activating caspases that mediate apoptosis, and Review
Coronary microvascular dysfunction is prevalent among diabetics and is correlated with cardiac mo... more Coronary microvascular dysfunction is prevalent among diabetics and is correlated with cardiac mortality. Compromised endothelial-dependent dilation (EDD) is an early event in the progression of diabetes, but the mechanisms remain incompletely understood. Nitric oxide (NO) is the major endothelium-dependent vasodilatory metabolite in the healthy coronary circulation, but switches to hydrogen peroxide (H2O2) in coronary artery disease (CAD) patients. Because diabetes is a major risk factor for CAD we hypothesized that a similar switch from NO-to-H2O2 occurs in diabetes. Methods: Vasodilation was measured ex vivo in isolated coronary arteries from wild type (WT) and microRNA-21 (miR-21) null mice fed chow or high fat and sugar diet, and LepR null (db/db) mice using myography. Myocardial blood flow (MBF), blood pressure, and heart rate were measured in vivo using contrast echocardiography and a solid-state pressure sensor catheter. RNA from coronary arteries, endothelial cells and hear...
Reactive oxygen species and reactive nitrogen species are biological molecules that play importan... more Reactive oxygen species and reactive nitrogen species are biological molecules that play important roles in cardiovascular physiology and contribute to disease initiation, progression, and severity. Because of their ephemeral nature and rapid reactivity, these species are difficult to measure directly with high accuracy and precision. In this statement, we review current methods for measuring these species and the secondary products they generate and suggest approaches for measuring redox status, oxidative stress, and the production of individual reactive oxygen and nitrogen species. We discuss the strengths and limitations of different methods and the relative specificity and suitability of these methods for measuring the concentrations of reactive oxygen and reactive nitrogen species in cells, tissues, and biological fluids. We provide specific guidelines, through expert opinion, for choosing reliable and reproducible assays for different experimental and clinical situations. Thes...
Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free r... more Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we ...
Mitochondrial reactive oxygen species (ROS) have emerged as an important mechanism of disease and... more Mitochondrial reactive oxygen species (ROS) have emerged as an important mechanism of disease and redox signaling in the cardiovascular system. Under basal or pathological conditions, electron leakage for ROS production is primarily mediated by the electron transport chain and the proton motive force consisting of a membrane potential (ΔΨ) and a proton gradient (ΔpH). Several factors controlling ROS production in the mitochondria include flavin mononucleotide and flavin mononucleotide–binding domain of complex I, ubisemiquinone and quinone-binding domain of complex I, flavin adenine nucleotide–binding moiety and quinone-binding pocket of complex II, and unstable semiquinone mediated by the Q cycle of complex III. In mitochondrial complex I, specific cysteinyl redox domains modulate ROS production from the flavin mononucleotide moiety and iron–sulfur clusters. In the cardiovascular system, mitochondrial ROS have been linked to mediating the physiological effects of metabolic dilation...
Background— Nitric oxide (NO) production is increased in postischemic myocardium, and NO can cont... more Background— Nitric oxide (NO) production is increased in postischemic myocardium, and NO can control mitochondrial oxygen consumption in vitro. Therefore, we investigated the role of endothelial NO synthase (eNOS)–derived NO on in vivo regulation of oxygen consumption in the postischemic heart. Methods and Results— Mice were subjected to 30 minutes of coronary ligation followed by 60 minutes of reperfusion. Myocardial oxygen tension (P o 2 ) was monitored by electron paramagnetic resonance oximetry. In wild-type, N -nitro- l -arginine methyl ester (L-NAME)–treated (with 1 mg/mL in drinking water), and eNOS knockout (eNOS −/− ) mice, no difference was observed among baseline myocardial P o 2 values (8.6±0.7, 10.0±1.2, and 10.1±1.2 mm Hg, respectively) or those measured at 30 minutes of ischemia (1.4±0.6, 2.3±0.9, and 3.1±1.4 mm Hg, respectively). After reperfusion, myocardial P o 2 increased markedly ( P <0.001 versus baseline in each group) but was much lower in L-NAME–treated an...
Mitochondria are the powerhouses of the living cell, producing most of the cell’s energy by oxida... more Mitochondria are the powerhouses of the living cell, producing most of the cell’s energy by oxidative phosphorylation. The process of energy transduction requires the coordinated action of 4 major respiratory enzyme complexes and ATP synthase (F 0 F 1 ATPase). High-resolution structures are now available for the bacterial complex I, complete structures of mammalian complexes II to IV, and F 1 ATPase (peripheral or headpiece domain of F 0 F 1 ATPase). In addition, the mitochondria play a central role in the regulation of programmed cell death. The mitochondria trigger apoptosis by impairing electron transport and energy metabolism, by releasing cytochrome c and activating caspases that mediate apoptosis, and Review
Coronary microvascular dysfunction is prevalent among diabetics and is correlated with cardiac mo... more Coronary microvascular dysfunction is prevalent among diabetics and is correlated with cardiac mortality. Compromised endothelial-dependent dilation (EDD) is an early event in the progression of diabetes, but the mechanisms remain incompletely understood. Nitric oxide (NO) is the major endothelium-dependent vasodilatory metabolite in the healthy coronary circulation, but switches to hydrogen peroxide (H2O2) in coronary artery disease (CAD) patients. Because diabetes is a major risk factor for CAD we hypothesized that a similar switch from NO-to-H2O2 occurs in diabetes. Methods: Vasodilation was measured ex vivo in isolated coronary arteries from wild type (WT) and microRNA-21 (miR-21) null mice fed chow or high fat and sugar diet, and LepR null (db/db) mice using myography. Myocardial blood flow (MBF), blood pressure, and heart rate were measured in vivo using contrast echocardiography and a solid-state pressure sensor catheter. RNA from coronary arteries, endothelial cells and hear...
Reactive oxygen species and reactive nitrogen species are biological molecules that play importan... more Reactive oxygen species and reactive nitrogen species are biological molecules that play important roles in cardiovascular physiology and contribute to disease initiation, progression, and severity. Because of their ephemeral nature and rapid reactivity, these species are difficult to measure directly with high accuracy and precision. In this statement, we review current methods for measuring these species and the secondary products they generate and suggest approaches for measuring redox status, oxidative stress, and the production of individual reactive oxygen and nitrogen species. We discuss the strengths and limitations of different methods and the relative specificity and suitability of these methods for measuring the concentrations of reactive oxygen and reactive nitrogen species in cells, tissues, and biological fluids. We provide specific guidelines, through expert opinion, for choosing reliable and reproducible assays for different experimental and clinical situations. Thes...
Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free r... more Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we ...
Mitochondrial reactive oxygen species (ROS) have emerged as an important mechanism of disease and... more Mitochondrial reactive oxygen species (ROS) have emerged as an important mechanism of disease and redox signaling in the cardiovascular system. Under basal or pathological conditions, electron leakage for ROS production is primarily mediated by the electron transport chain and the proton motive force consisting of a membrane potential (ΔΨ) and a proton gradient (ΔpH). Several factors controlling ROS production in the mitochondria include flavin mononucleotide and flavin mononucleotide–binding domain of complex I, ubisemiquinone and quinone-binding domain of complex I, flavin adenine nucleotide–binding moiety and quinone-binding pocket of complex II, and unstable semiquinone mediated by the Q cycle of complex III. In mitochondrial complex I, specific cysteinyl redox domains modulate ROS production from the flavin mononucleotide moiety and iron–sulfur clusters. In the cardiovascular system, mitochondrial ROS have been linked to mediating the physiological effects of metabolic dilation...
Background— Nitric oxide (NO) production is increased in postischemic myocardium, and NO can cont... more Background— Nitric oxide (NO) production is increased in postischemic myocardium, and NO can control mitochondrial oxygen consumption in vitro. Therefore, we investigated the role of endothelial NO synthase (eNOS)–derived NO on in vivo regulation of oxygen consumption in the postischemic heart. Methods and Results— Mice were subjected to 30 minutes of coronary ligation followed by 60 minutes of reperfusion. Myocardial oxygen tension (P o 2 ) was monitored by electron paramagnetic resonance oximetry. In wild-type, N -nitro- l -arginine methyl ester (L-NAME)–treated (with 1 mg/mL in drinking water), and eNOS knockout (eNOS −/− ) mice, no difference was observed among baseline myocardial P o 2 values (8.6±0.7, 10.0±1.2, and 10.1±1.2 mm Hg, respectively) or those measured at 30 minutes of ischemia (1.4±0.6, 2.3±0.9, and 3.1±1.4 mm Hg, respectively). After reperfusion, myocardial P o 2 increased markedly ( P <0.001 versus baseline in each group) but was much lower in L-NAME–treated an...
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