Increased Reactive Oxygen Species Production and Functional Alterations in Antioxidant Enzymes in Human Failing Myocardium

Sam, Flora; Kerstetter, David; Pimental, David R.; Mulukutla, Suresh; Tabaee, Arash; Bristow, Michael R.; Colucci, Wilson S.; Sawyer, Douglas B.

doi:10.1016/j.cardfail.2005.01.007

Cited by 175 publications

(121 citation statements)

References 39 publications

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“…Dissociation between metabolic genes and protein expression has been shown to exist. 55 Another reason for our findings may be that, similar to antioxidant enzymes in HF, 56 decreased UCP3 and MCAD protein expression reflects decreased translation or posttranslational modification of metabolic enzymes. 57,58 Additionally, our findings may differ because of the model of HF (diastolic versus systolic), method of inducing HF (aldosterone infusion versus pacing induced 59 ), and animal species (mice versus dogs).…”

Section: Lebrasseur Et Almentioning

confidence: 94%

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

et al. 2007

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Abstract-Hypertension and cardiac remodeling are associated with myocardial fibrosis, left ventricular (LV) hypertrophy, and diastolic heart failure. Fenofibrate suppresses aldosterone-mediated increases in myocyte matrix metalloproteinase activity and extracellular signal-regulated kinase phosphorylation. It is unknown whether the peroxisome proliferatoractivated receptor-␣ agonist, fenofibrate, improves cardiac remodeling in a model of aldosterone-induced hypertension and LV hypertrophy. Twelve-week-old uninephrectomized FVB mice received 1% NaCl drinking water. Miniosmotic pumps delivered saline or aldosterone for 4 weeks. Mice were either untreated (nϭ14) or treated with fenofibrate 100 mg/kg per day (nϭ12) for 1 week before and 4 weeks after surgery. Key Words: fibrosis Ⅲ aldosterone Ⅲ hypertension Ⅲ cardiac remodeling Ⅲ matrix metalloproteinases Ⅲ peroxisome proliferator-activated receptor-␣ D iastolic heart failure (HF) refers to "HF with preserved left ventricular (LV) ejection fraction" 1-3 and is observed in almost half of the patients who present with clinical HF. 2 Hypertension, a significant risk factor for diastolic dysfunction and HF, 4 is frequently associated with cardiac remodeling and LV hypertrophy (LVH). 5 Similarly, LVH and diastolic dysfunction are associated with matrix metalloproteinase (MMP) activation that favors decreased extracellular matrix degradation and increased interstitial collagen, 6 thus perpetuating fibrosis. Tissue inhibitors of metalloproteinases (TIMPs) may predict HF in chronic hypertension. 7 Likewise, aldosterone antagonists (used in chronic HF and in hypertension) exert positive effects by downregulating MMP activity. 8 -11 Despite the increasing incidence of diastolic HF and elevated mortality rates, 12 there remains a paucity of therapies that target these potential underlying mechanism(s).Fenofibrate, a peroxisome proliferator-activated receptor-␣ (PPAR-␣) agonist, is used clinically for the treatment of dyslipidemias. Intriguingly, fibrates are being considered as possible therapeutic agents for the treatment of cardiac remodeling. 13 The myocardial effects of fenofibrate are independent of its lipid-lowering actions and are partly due to PPAR-␣-mediated suppression of inflammatory transcription factors (eg, nuclear factor-B and activating protein-1) 14 -16 and inhibition of macrophage recruitment. 17 Inhibition of nuclear factor-B with fenofibrates in hypertension prevents the development of diastolic dysfunction. 18 We previously demonstrated in isolated adult cardiomyocytes that fenofibrate

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Section: Lebrasseur Et Almentioning

confidence: 94%

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

et al. 2007

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“…This allows a higher oxidant load to be tolerated and alleviates the negative effects of increased ROS. The potential importance of Nrf2 as a regulator of redox homeostasis is suggested in a study of failing human hearts where, concomitant with persistent increases in ROS levels, the activity of Nrf2-regulated antioxidant enzymes were shown to decline (105).…”

Section: Oxido-reductive Pathways In Heartmentioning

confidence: 99%

Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

Brewer

Mustafi

Murray

et al. 2013

Antioxidants & Redox Signaling

107

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Significance: Aerobic organisms must exist between the dueling biological metabolic processes for energy and respiration and the obligatory generation of reactive oxygen species (ROS) whose deleterious consequences can reduce survival. Wide fluctuations in harmful ROS generation are circumvented by endogenous countermeasures (i.e., enzymatic and nonenzymatic antioxidants systems) whose capacity decline with aging and are enhanced by disease states. Recent Advances: Substantial efforts on the cellular and molecular underpinnings of oxidative stress has been complemented recently by the discovery that reductive stress similarly predisposes to inheritable cardiomyopathy, firmly establishing that the biological extremes of the redox spectrum play essential roles in disease pathogenesis. Critical Issues: Because antioxidants by nutritional or pharmacological supplement to prevent or mitigate disease states have been largely disappointing, we hypothesize that lack of efficacy of antioxidants might be related to adverse outcomes in responders at the reductive end of the redox spectrum. As emerging concepts, such as reductive, as opposed, oxidative stress are further explored, there is an urgent and critical gap for biochemical phenotyping to guide the targeted clinical applications of therapeutic interventions. Future Directions: New approaches are vitally needed for characterizing redox states with the long-term goal to noninvasively assess distinct clinical states (e.g., presymptomatic, end-stage) with the diagnostic accuracy to guide personalized medicine.

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“…In the failing ventricular myocard from patients with end-stage heart failure a marked decline in mitochondrial Mn-SOD protein and activity is detected [138]. Mitochondrial biogenesis is also severely impaired as evidenced by reduced mtDNA replication and depletion of mtDNA in the human failing heart [139].…”

Section: Mitochondrial Ros Production and Angiotensin II In Cardiac Fmentioning

confidence: 99%

Modulation of Reactive Oxygen Species and Collagen Synthesis by Angiotensin II in Cardiac Fibroblasts

Lijnen¹

2011

TOHYPERJ

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Angiotensin II increases the NAD(P)H-dependent superoxide anion production and the intracellular generation of reactive oxygen species in cardiac fibroblasts and apocynin, a NAD(P)H oxidase inhibitor, abrogates this rise. The membrane associated NAD(P)H oxidase complex is the predominant source of superoxide anion and reactive oxygen species generation in angiotensin II-stimulated adult cardiac fibroblasts. Inhibition of this NAD(P)H oxidase complex with apocynin completely blocks the angiotensin II-stimulated collagen production, collagen I and III protein and mRNA expression.Superoxide anion production is also increased by the Cu,Zn-superoxide dismutase (SOD) inhibitor diethyldithiocarbamic acid (DETC) and decreased by the superoxide scavenger tempol in control and ANG II-treated fibroblasts. ANG II and DETC stimulate the collagen production and the collagen I and fibronectin content in fibroblasts. The SOD mimetics tempol and EUK-8 as well as polyethyleneglycol-SOD reduce the collagen production.ANG II also decreases the activity and mRNA and protein expression of the mitochondrial antioxidants Mn-SOD and peroxiredoxin-3. Upon phosphorylation of Akt by ANG II, P-Akt is translocated from the cytoplasm to the nucleus and nuclear phosphorylation of FOXO3a by P-Akt leads to relocalisation of FOXO3a from the nucleus to the cytosol, resulting in a decrease in its transcriptional activity and in Mn-SOD expression. These data indicate that ANG II inactivates FOXO3a by activating Akt and this leads to a reduction in the expression of the antioxidant Mn-SOD. A role of SOD and the formed reactive oxygen species in the regulation and organization of collagen in cardiac fibroblasts is suggested.

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Increased Reactive Oxygen Species Production and Functional Alterations in Antioxidant Enzymes in Human Failing Myocardium

Cited by 175 publications

References 39 publications

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

Modulation of Reactive Oxygen Species and Collagen Synthesis by Angiotensin II in Cardiac Fibroblasts

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