NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity

Hafstad, Anne Dragøy; Hansen, Synne Simonsen; Lund, Jim; Santos, Célio X.C.; Boardman, Neoma T.; Shah, Ajay M.; Aasum, Ellen

doi:10.3390/antiox9020171

Cited by 12 publications

(8 citation statements)

References 56 publications

(99 reference statements)

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“…In a previous study performed by our group, we demonstrated that ablation and pharmacological inhibition of NOX2 in obese mice improved the mechanical efficiency and reduced myocardial oxygen consumption (MVO 2 ) for non-mechanical cardiac work [ 23 ]. We have also previously demonstrated an association between increased ROS and increased MVO 2 [ 14 ], which together suggest a link between myocardial oxygen wasting and NOX2 activation.…”

Section: Discussionmentioning

confidence: 99%

“…Although there are several sources of ROS in cardiomyocytes, studies have confirmed that NADPH oxidase 2 (NOX2) is a crucial contributor to AngII-induced ROS production in the pathogenesis of heart failure [ 20 , 21 , 22 ]. We have previously found elevated myocardial ROS levels to be associated with increased myocardial oxygen consumption [ 14 ], and abrogation of NOX2 was shown to reduce cardiac ROS levels and improve cardiac efficiency in obesity-induced heart-failure [ 23 ]. Furthermore, non-pressor doses of AngII (50 ng/kg/min) have been shown to induce mitochondrial uncoupling in skeletal muscles [ 19 ], which could suggest an impact on mitochondrial efficiency.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling

et al. 2022

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The present study aimed to examine the effects of low doses of angiotensin II (AngII) on cardiac function, myocardial substrate utilization, energetics, and mitochondrial function in C57Bl/6J mice and in a transgenic mouse model with cardiomyocyte specific upregulation of NOX2 (csNOX2 TG). Mice were treated with saline (sham), 50 or 400 ng/kg/min of AngII (AngII50 and AngII400) for two weeks. In vivo blood pressure and cardiac function were measured using plethysmography and echocardiography, respectively. Ex vivo cardiac function, mechanical efficiency, and myocardial substrate utilization were assessed in isolated perfused working hearts, and mitochondrial function was measured in left ventricular homogenates. AngII50 caused reduced mechanical efficiency despite having no effect on cardiac hypertrophy, function, or substrate utilization. AngII400 slightly increased systemic blood pressure and induced cardiac hypertrophy with no effect on cardiac function, efficiency, or substrate utilization. In csNOX2 TG mice, AngII400 induced cardiac hypertrophy and in vivo cardiac dysfunction. This was associated with a switch towards increased myocardial glucose oxidation and impaired mitochondrial oxygen consumption rates. Low doses of AngII may transiently impair cardiac efficiency, preceding the development of hypertrophy induced at higher doses. NOX2 overexpression exacerbates the AngII -induced pathology, with cardiac dysfunction and myocardial metabolic remodelling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling

et al. 2022

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“…Our present study also exhibited increased mitochondrial ROS production and NADPH oxidase (NOX) activity that generated ROS, and increased LPO in the pancreas and heart of GK diabetic rats. Studies have shown increased NOX activity to be associated with impaired calcium signaling and hyperglycemia-induced cardiomyocyte apoptosis and mitochondrial dysfunction, as well as the regulation of insulin secretion in pancreatic cells [ 36 , 37 , 56 ]. In addition to hyperglycemia, dyslipidemia has also been associated with NOX activation [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Aspirin on Mitochondrial Dysfunction and Stress in the Pancreas and Heart of Goto-Kakizaki Diabetic Rats

John

Amiri

Shafarin

et al. 2021

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Our previous study in Goto-Kakizaki (GK) type 2 diabetic rats provided significant evidence that aspirin treatment improves pancreatic β-cell function by reducing inflammatory responses and improving glucose tolerance. In the present study, we aimed to elucidate the mechanism of action of aspirin on the pathophysiology and progression of type 2 diabetic complications in the heart and pancreas of insulin-resistant GK rats. Aspirin treatment demonstrated a reduction in mitochondrial reactive oxygen species (ROS) production and lipid peroxidation, accompanied by improved redox homeostasis. Furthermore, the recovery of metabolic and mitochondrial functions, as well as cytochrome P450 enzyme activities, which were altered in the pancreas and heart of GK rats, were observed. Aspirin treatment brought the activity of CYP 2E1 to the control level in both tissues, whereas the CYP 3A4 level decreased only in the pancreas. This suggests the tissue-specific differential metabolism of substrates in these rats. The recovery of redox homeostasis could be the key target in the improvement of oxidative-stress-dependent alterations in mitochondrial functions which, in turn, facilitated improved energy metabolism in these tissues in the aspirin-treated GK rats. These results may have implications in determining the therapeutic use of aspirin, either alone or in combination with other clinically approved therapies, in insulin-resistant type 2 diabetes.

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“…Basic science studies implicate NOX2, NOX4, and NOX5 in the deterioration of diastolic function and adverse cardiac remodeling in response to pathological stimuli ( Table 2 ). A global loss of Nox2 limits myocardial ROS production and preserves diastolic function in response to diet-induced obesity [ 87 ], doxorubicin treatment [ 88 ], and myocardial infarction [ 89 ], and mitigates cardiac fibrosis in response to AngII, aldosterone, or pressure overload [ 41 , 90 , 91 , 92 ], whereas Nox2 overexpression in endothelial cells promotes cardiac fibrosis, inflammation, and diastolic dysfunction in response to AngII [ 93 ]. Inducible NOX2 activity in the heart in response to AngII appears to be particularly important for adverse cardiac remodeling and oxidative stress, as the loss of Nox2 protects from AngII-induced myocardial oxidative stress, hypertrophy, and fibrosis without altering AngII-induced hypertension [ 41 ].…”

Section: Nadph Oxidases In Cardiovascular Diseasementioning

confidence: 99%

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction

et al. 2022

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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases regulate production of reactive oxygen species (ROS) that cause oxidative damage to cellular components but also regulate redox signaling in many cell types with essential functions in the cardiovascular system. Research over the past couple of decades has uncovered mechanisms by which NADPH oxidase (NOX) enzymes regulate oxidative stress and compartmentalize intracellular signaling in endothelial cells, smooth muscle cells, macrophages, cardiomyocytes, fibroblasts, and other cell types. NOX2 and NOX4, for example, regulate distinct redox signaling mechanisms in cardiac myocytes pertinent to the onset and progression of cardiac hypertrophy and heart failure. Heart failure with preserved ejection fraction (HFpEF), which accounts for at least half of all heart failure cases and has few effective treatments to date, is classically associated with ventricular diastolic dysfunction, i.e., defects in ventricular relaxation and/or filling. However, HFpEF afflicts multiple organ systems and is associated with systemic pathologies including inflammation, oxidative stress, arterial stiffening, cardiac fibrosis, and renal, adipose tissue, and skeletal muscle dysfunction. Basic science studies and clinical data suggest a role for systemic and myocardial oxidative stress in HFpEF, and evidence from animal models demonstrates the critical functions of NOX enzymes in diastolic function and several HFpEF-associated comorbidities. Here, we discuss the roles of NOX enzymes in cardiovascular cells that are pertinent to the development and progression of diastolic dysfunction and HFpEF and outline potential clinical implications.

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NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity

Cited by 12 publications

References 56 publications

Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling

Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling

Effect of Aspirin on Mitochondrial Dysfunction and Stress in the Pancreas and Heart of Goto-Kakizaki Diabetic Rats

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction

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