Oxidative stress in multiple organs after sepsis in elderly rats

Margotti, Willian; Machado, Richard Simon; Bagio, Érick; Dacoregio, Carlos; Bernades, Gabriela Costa; Lanzzarin, Everton; Stork, Solange; Cidreira, Thainá; Denicol, Taís; Joaquim, Larissa; Danielski, Lucinéia Gainski; Metzker, Kiuanne Lino Lobo; Bonfante, Sandra; Margotti, Edficher; Petronilho, Fabrícia

doi:10.1016/j.exger.2022.111705

Cited by 9 publications

(7 citation statements)

References 74 publications

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“…It is likely that inflamm-aging involves the alteration of other TLRs, including TLR4. A recent report shows that older rats (7 month old) have greater oxidative stress in multiple organs, including the heart, following CLP ( 26 ). Thus, inhibition of TLR2 alone would attenuate, rather than abrogate, cardiac dysfunction in old septic subject.…”

Section: Discussionmentioning

confidence: 99%

Aging exacerbates cardiac dysfunction and mortality in sepsis through enhancing TLR2 activity

Zhai,

Yao,

The

et al. 2023

Front. Cardiovasc. Med.

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IntroductionSepsis is prevalent in the elderly population with increased incidence and mortality. Currently, the mechanism by which aging increases the susceptibility to sepsis and worsens outcome is unclear. We tested the hypothesis that aging exacerbates cardiac dysfunction in sepsis through a Toll-like receptor 2 (TLR2)-dependent mechanism.MethodsMale young adult (4–6 months) and old (18–20 months) wild type (WT) and TLR2 knockout (KO) mice were subject to moderate sepsis by cecal ligation and puncture. Additional groups of young adult and old WT mice were treated with TLR2 agonist Pam3CSK4. Left ventricle (LV) performance was evaluated with a pressure-volume microcatheter. Tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in the myocardium and plasma were assessed using enzyme-linked immunosorbent assay.ResultsSepsis reduced LV ejection fraction and cardiac output in both young adult and old WT mice. However, identical CLP caused more severe cardiac dysfunction and high mortality in old WT mice that were accompanied by greater levels of TNF-α, IL-1β, IL-6 and MCP-1 in the myocardium and plasma. TLR2 KO diminished aging-related difference in myocardial and systemic inflammatory response, resulting in improved cardiac function and decreased mortality in old septic mice. In addition, higher myocardial TLR2 levels in old WT mice resulted in greater myocardial inflammatory response and worse cardiac dysfunction following administration of TLR2 agonist.ConclusionModerate sepsis results in greater cardiac dysfunction and significant mortality in old mice. Aging elevates TLR2 level/activity to exacerbate the inflammatory response to sepsis, leading to worse cardiac dysfunction and mortality.

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Section: Discussionmentioning

confidence: 99%

Aging exacerbates cardiac dysfunction and mortality in sepsis through enhancing TLR2 activity

Zhai,

Yao,

The

et al. 2023

Front. Cardiovasc. Med.

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“…Indeed, in the setting of Gram-negative bacteremia and sepsis, the onset of myocardial depression and ventricular dilatation following an outflow of cytokines (IL1 β , IL-6, and TNF α ), nitric oxide, and endotoxins has been reported. Other low-significant theories such as activation of free and superoxide radicals are reported in experimental studies involving rats [ 59 ]. Ventricular wall stress-mediated is likewise postulated in human settings [ 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Cardiac Troponin I and Electrocardiographic Evaluation in Hospitalized Cats with Systemic Inflammatory Response Syndrome

Pugliese,

Napoli,

La Maestra

et al. 2023

Veterinary Sciences

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Several studies conducted on humans demonstrate the increase in cardiac troponins and the onset of arrhythmias in the course of systemic inflammatory response syndrome (SIRS). The aim of the current study was to assess the blood concentration of cardiac troponin I (cTnI) and electrocardiographic findings in SIRS-affected cats. Seventeen shorthair cats hospitalized with SIRS were enrolled (Group 1). SIRS diagnosis was performed based on the detection of at least two of the four criteria such as abnormal body temperature, abnormal heart rate (i.e., tachycardia or bradycardia), abnormal respiratory rate (i.e., tachypnea or bradypnea), and alterations of white blood cell number (i.e., leukocytes or band neutrophils). Ten cats screened for elective surgery such as neutering or dental procedures were evaluated as a control population (Group 2). They were considered healthy based on history, physical examination, hematological and biochemical profile, urinalysis, coprological exam, thyroxine assay, blood pressure measurement, and echocardiography. A physical examination, complete blood cell count, biochemistry test (including an electrolyte panel), electrocardiographic examination, and cTnI assay were carried out in each cat enrolled. Traumatic events, gastrointestinal, neoplastic, respiratory, and neurological disorders were identified as causes of SIRS in Group 1. In Group 1, a significantly higher concentration of cTnI than that in Group 2 was recorded (p = 0.004). In 37.5% of cats with SIRS, ventricular premature complexes occurring in couplets with multiform configuration were detected. Similarly, to humans, data herein reported would indicate possible cardiac damage present in cats with SIRS diagnosis.

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“…Specifically, the rodent heart also becomes hypertrophic with age and there is a substantial decline in systolic and diastolic function (4)(5)(6)(7). Additionally, the role of oxidative stress, proteostasis, and mitochondrial dysfunction have been shown to influence cardiac and system wide functions in both animal models and humans (8)(9)(10)(11)(12). Because aging, per se, is the major risk factor for the development of the most common CVDs (13)(14)(15), there is a need for further development of safe interventions that will antagonize the effects of inflammation that underpins age-associated changes in cardiac structure and function.…”

Section: Introductionmentioning

confidence: 99%

A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan

Winicki

Nanavati

Morrell

et al. 2023

Front. Cardiovasc. Med.

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BackgroundAging is associated with increased levels of reactive oxygen species and inflammation that disrupt proteostasis and mitochondrial function and leads to organism-wide frailty later in life. ARA290 (cibinetide), an 11-aa non-hematopoietic peptide sequence within the cardioprotective domain of erythropoietin, mediates tissue protection by reducing inflammation and fibrosis. Age-associated cardiac inflammation is linked to structural and functional changes in the heart, including mitochondrial dysfunction, impaired proteostasis, hypertrophic cardiac remodeling, and contractile dysfunction. Can ARA290 ameliorate these age-associated cardiac changes and the severity of frailty in advanced age?MethodsWe conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline. Serial echocardiography, tail blood pressure and body weight were evaluated repeatedly at 4-month intervals. A frailty index was calculated at the final timepoint (33 months of age). Tissues were harvested at 4-month intervals to define inflammatory markers and left ventricular tissue remodeling. Mitochondrial and myocardial cell health was assessed in isolated left ventricular myocytes. Kaplan–Meier survival curves were established. Mixed ANOVA tests and linear mixed regression analysis were employed to determine the effects of age, treatment, and age-treatment interactions.ResultsChronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines, total NF-κB, and p-NF-κB. Additionally, ARA290 treatment enhanced cardiomyocyte autophagy flux and reduced cellular accumulation of lipofuscin. The cardiomyocyte mitochondrial permeability transition pore response to oxidant stress was desensitized following chronic ARA290 treatment. Concurrently, ARA290 significantly blunted the age-associated elevation in blood pressure and preserved the LV ejection fraction. Finally, ARA290 preserved body weight and significantly reduced other markers of organism-wide frailty at the end of life.ConclusionAdministration of ARA290 reduces cell and tissue inflammation, mitigates structural and functional changes within the cardiovascular system leading to amelioration of frailty and preserved healthspan.

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Oxidative stress in multiple organs after sepsis in elderly rats

Cited by 9 publications

References 74 publications

Aging exacerbates cardiac dysfunction and mortality in sepsis through enhancing TLR2 activity

Aging exacerbates cardiac dysfunction and mortality in sepsis through enhancing TLR2 activity

Cardiac Troponin I and Electrocardiographic Evaluation in Hospitalized Cats with Systemic Inflammatory Response Syndrome

A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan

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