TNF-α inhibitors reduce inflammation-induced concentric remodelling, but not diastolic dysfunction in collagen-induced arthritis

Roux, Regina Le; Mokotedi, Lebogang; Fourie, Serena; Manilall, Ashmeetha; Gunter, Sulé; Millen, Aletta M E

doi:10.55563/clinexprheumatol/l4nnv0

Cited by 8 publications

(19 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The control group (n = 26, males n = 14, females n = 12) received a subcutaneous injection of saline (0.2 ml). A modified Chondrex collagen inoculation protocol was employed to induce systemic inflammation in the experimental group, as previously described [23,24]. Briefly, the experimental group was injected subcutaneously at the base of the tail with Bovine type II collagen (2 mg/ml in 0.05 M acetic acid) emulsified in incomplete Freund's adjuvant (1:1 volume, 0.2 ml).…”

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

“…The non-invasive tail-cuff technique was used to measure blood pressure biweekly (Biopac Systems, Santa Barbara, CA, USA). The rats used in the current study are part of a larger study of the effects of collagen-induced systemic inflammation and, in accordance with ethics committee recommendations to minimize numbers of animals used, echocardiography data for a subset (n = 64) of the rats used in the current study have been previously reported [24].…”

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

“…Rats were anaesthetized by intramuscular injections of ketamine (100 mg kg −1 ) and xylazine (5 mg kg −1 ). LV diastolic function was determined by echocardiography (Acuson SC 2000, Siemens Medical Solutions, USA, Inc.) by an experienced observer who was blinded to the treatment groups, as previously described [24,25]. Briefly, LV diastolic function was assessed using pulsed Doppler, tissue Doppler imaging (TDI) and left atrial volume.…”

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

“…LV stiffness was expressed as the lateral wall e′/a′ ratio. LV relaxation and LV filling pressure were indexed by lateral wall e′ and E/e′, respectively [24,25]. Following echocardiography, rats were sacrificed with an overdose of anaesthesia (ketamine 200 mg kg −1 and xylazine 10 mg kg −1 ) followed by thoracotomy and the left ventricle of the hearts was dissected and stored (− 80 °C) in RNAlater ® (Ambion, Sigma Aldrich, Germany).…”

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

“…Blood was centrifuged and serum was collected and stored at − 80 °C. Sandwich enzyme-linked immunosorbent assays (ELISA, Elabscience Biotechnology, USA) were used for duplicate measurements of serum CRP, TNF-α, and IL-6 concentrations [24,26].…”

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

See 4 more Smart Citations

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

Manilall

Mokotedi

Gunter

et al. 2022

BMC Cardiovasc Disord

Self Cite

View full text Add to dashboard Cite

Background Titin phosphorylation contributes to left ventricular (LV) diastolic dysfunction. The independent effects of inflammation on the molecular pathways that regulate titin phosphorylation are unclear. Methods We investigated the effects of collagen-induced inflammation and subsequent tumor necrosis factor-α (TNF-α) inhibition on mRNA expression of genes involved in regulating titin phosphorylation in 70 Sprague-Dawley rats. LV diastolic function was assessed with echocardiography. Circulating inflammatory markers were quantified by enzyme-linked immunosorbent assay and relative LV gene expression was assessed by Taqman® polymerase chain reaction. Differences in normally distributed variables between the groups were determined by two-way analysis of variance (ANOVA), followed by Tukey post-hoc tests. For non-normally distributed variables, group differences were determined by Kruskal–Wallis tests. Results Collagen inoculation increased LV relative mRNA expression of vascular cell adhesion molecule 1 (VCAM1), pentraxin 3 (PTX3), and inducible nitric oxide synthase (iNOS) compared to controls, indicating local microvascular inflammation. Collagen inoculation decreased soluble guanylate cyclase alpha-2 (sGCα2) and soluble guanylate cyclase beta-2 (sGCβ2) expression, suggesting downregulation of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling. Inhibiting TNF-α prevented collagen-induced changes in VCAM1, iNOS, sGCα2 and sGCβ2 expression. Collagen inoculation increased protein phosphatase 5 (PP5) expression. Like LV diastolic dysfunction, increased PP5 expression was not prevented by TNF-α inhibition. Conclusion Inflammation-induced LV diastolic dysfunction may be mediated by a TNF-α-independent increase in PP5 expression and dephosphorylation of the N2-Bus stretch element of titin, rather than by TNF-α-induced downregulation of NO-sGC-cGMP pathway-dependent titin phosphorylation. The steady rise in number of patients with inflammation-induced diastolic dysfunction, coupled with low success rates of current therapies warrants a better understanding of the systemic signals and molecular pathways responsible for decreased titin phosphorylation in development of LV diastolic dysfunction. The therapeutic potential of inhibiting PP5 upregulation in LV diastolic dysfunction requires investigation.

show abstract

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

Section: Animal Treatment and Confirmation Of Systemic Inflammation A...mentioning

confidence: 99%

See 3 more Smart Citations

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

Manilall

Mokotedi

Gunter

et al. 2022

BMC Cardiovasc Disord

Self Cite

View full text Add to dashboard Cite

show abstract

Association of the TNF‐α‐308G>A gene polymorphism with left ventricular geometry and functional abnormalities in obstructive sleep apnea subjects

Chen,

Wang,

Shui

et al. 2023

J of Clinical Ultrasound

View full text Add to dashboard Cite

ObjectiveTumor necrosis factor‐α (TNF‐α) can induce left ventricular remodeling. In this study, we investigated whether the TNF‐α‐308G>A polymorphism is associated with left ventricular geometry (LVG) and left ventricular functional abnormalities in obstructive sleep apnea (OSA) subjects.MethodsTwo hundred and seventy‐eight subjects were enrolled. Echocardiography and genetic data were assessed in all patients. Geometric patterns of the left ventricle were determined from the relative wall thickness and left ventricular mass index (LVMI). Genetic analysis for the TNF‐α‐308G>A SNP rs1800629 was identified by Sanger sequencing. The correlations of the TNF‐α‐308G>A polymorphism with LVG and left ventricular function were analyzed by difference analysis and logistic regression.ResultsThe chi‐square test showed that there were differences in genotype distributions among the four groups (p = 0.033), such that the frequency of GA+AA genotypes was significantly higher in the concentric hypertrophy group than in the normal geometry group (p < 0.05). Independent sample T tests showed that the GA+AA genotypes had higher IVST, LVPWT, LVMI, E/e' values, and lower e' values than those of the GG genotype (p < 0.05). Logistic regression analysis showed that the TNF‐α‐308G>A polymorphism was independently correlated with eccentric hypertrophy (OR = 2.456, p = 0.047) and concentric hypertrophy (OR = 2.456, p = 0.047).ConclusionIn OSA patients, the TNF‐α‐308G>A polymorphism was linked to LVG and abnormal left ventricular diastolic function, suggesting that the TNF‐α‐308G>A polymorphism may have an important influence on LVG alterations.

show abstract

Tumor necrosis factor-α mediates inflammation-induced early-stage left ventricular systolic dysfunction

Manilall

Mokotedi

Gunter

et al. 2023

Journal of Cardiovascular Pharmacology

Self Cite

View full text Add to dashboard Cite

Elevated systemic inflammation contributes to pathogenesis of heart failure with preserved ejection fraction (HFpEF), but molecular mechanisms are poorly understood. Although left ventricular (LV) diastolic dysfunction is the main cause of HFpEF, subclinical systolic dysfunction also contributes. We have previously shown that rats with collagen-induced arthritis (CIA) have systemic inflammation, LV diastolic dysfunction, and that increased circulating TNF-a contributes to inflammation-induced HFpEF pathogenesis, but does not mediate LV diastolic dysfunction in CIA rats. Contribution of systemic inflammation to dysfunction of the active process of LV diastolic and systolic function are unknown. In the present study, we used the CIA rat model to investigate the effects of systemic inflammation and TNF-a blockade on systolic function, and mRNA expression of genes involved in active diastolic relaxation and of myosin heavy chain (MyHC) isoforms. Collagen inoculation and TNF-a blockade did not affect LV mRNA expression of genes that mediate active LV diastolic function. Collagen-induced inflammation impaired LV global longitudinal strain (P = 0.03) and velocity (P = 0.04). This impairment of systolic function was prevented by TNF-a blockade. Collagen inoculation decreased mRNA expression of a-MyHC (Myh6, P = 0.03) and increased expression of b-MyHC (Myh7, P = 0.0002), a marker, which is upregulated in failing hearts. TNF-a blockade prevented this MyHC isoformswitch. These results show that increased circulating TNF-a changes the relative expression of MyHC isoforms, favoring b-MyHC, which may underlie changes in contractile function that impair systolic function. Our results indicate that TNF-a initiates early-stage LV systolic, rather than LV diastolic dysfunction.

show abstract

TNF-α inhibitors reduce inflammation-induced concentric remodelling, but not diastolic dysfunction in collagen-induced arthritis

Cited by 8 publications

References 0 publications

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

Association of the TNF‐α‐308G>A gene polymorphism with left ventricular geometry and functional abnormalities in obstructive sleep apnea subjects

Tumor necrosis factor-α mediates inflammation-induced early-stage left ventricular systolic dysfunction

Contact Info

Product

Resources

About