Sustained Toll-Like Receptor 9 Activation Promotes Systemic and Cardiac Inflammation, and Aggravates Diastolic Heart Failure in SERCA2a KO Mice

Dhondup, Yangchen; Sjaastad, Ivar; Scott, Helge; Sandanger, Øystein; Zhang, Lili; Haugstad, Solveig Bjærum; Aronsen, Jan Magnus; Ranheim, Trine; Holmen, Sigve; Alfsnes, Kristian; Ahmed, Mohammed S.; Attramadal, Håvard; Gullestad, Lars; Aukrust, Pål; Christensen, Geir; Yndestad, Arne; Vinge, Leif Erik

doi:10.1371/journal.pone.0139715

Cited by 13 publications

(11 citation statements)

References 34 publications

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“…This, in turn, results in the release of large amounts of various pro-inflammatory cytokines and chemokines. In the animal model of experimentally induced left ventricular diastolic dysfunction, it was confirmed that the degree of diastolic dysfunction was associated with the degree of myocardial inflammation, of the intensity of pro-inflammatory cytokines expression and of myocardial infiltration by monocytes/macrophages [48]. The animal model used in this experiment does not allow the effects caused by direct TLR9 stimulation to be fully differentiated from the effects resulting from systemic inflammation.…”

Section: Toll-like Receptors and Inflammation In Hfmentioning

confidence: 77%

“…In the animal model of diastolic HF, it was confirmed, furthermore, that persistent activation of toll-like receptor 9 (TLR9) induces systemic and cardiac inflammatory response and increases diastolic dysfunction of the heart [48]. It is now believed that stimulation of both cardiac and non-cardiac TLR9 leads to the activation of NF-kB and interferon regulatory factor 3/7 (IRF 3/7).…”

Section: Toll-like Receptors and Inflammation In Hfmentioning

confidence: 98%

“…The animal model used in this experiment does not allow the effects caused by direct TLR9 stimulation to be fully differentiated from the effects resulting from systemic inflammation. It is emphasised, however, that the relationship between TLR9 stimulation and the severity of diastolic dysfunction is sufficiently proven [48].…”

Section: Toll-like Receptors and Inflammation In Hfmentioning

confidence: 99%

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Various aspects of inflammation in heart failure

et al. 2019

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Despite significant advances in the prevention and treatment of heart failure (HF), the prognosis in patients who have been hospitalised on at least one occasion due to exacerbation of HF is still poor. Therefore, a better understanding of the underlying pathophysiological mechanisms of HF is crucial in order to achieve better results in the treatment of this clinical syndrome. One of the areas that, for years, has aroused the interest of researchers is the activation of the immune system and the elevated levels of biomarkers of inflammation in patients with both ischaemic and non-ischaemic HF. Additionally, it is intriguing that the level of circulating pro-inflammatory biomarkers correlates with the severity of the disease and prognosis in this group of patients. Unfortunately, clinical trials aimed at assessing interventions to modulate the inflammatory response in HF have been disappointing, and the modulation of the inflammatory response has had either no effect or even a negative effect on the HF prognosis. The article presents a summary of current knowledge on the role of immune system activation and inflammation in the pathogenesis of HF. Understanding the immunological mechanisms pathogenetically associated with left ventricular remodelling and progression of HF may open up new therapeutic possibilities for HF.

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Section: Toll-like Receptors and Inflammation In Hfmentioning

confidence: 77%

Section: Toll-like Receptors and Inflammation In Hfmentioning

confidence: 98%

Section: Toll-like Receptors and Inflammation In Hfmentioning

confidence: 99%

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Various aspects of inflammation in heart failure

et al. 2019

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“…Finally, the cardiac myocyte SERCA2a KO model does not adequately represent the molecular basis for, or the clinical features of, diastolic HF." [214] Item 18. Generalisability/translation Comment on whether, and how, the findings of this study are likely to generalise to other species or experimental conditions, including any relevance to human biology (where appropriate).…”

Section: Explanationmentioning

confidence: 99%

Reporting animal research: Explanation and Elaboration for the ARRIVE guidelines 2019

Sert

Ahluwalia

Alam³

et al. 2019

Preprint

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Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting are vital to this process; it allows readers to assess the reliability of the findings, and repeat or build upon the work of other researchers. The NC3Rs developed the ARRIVE guidelines in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments.Despite widespread endorsement by the scientific community, the impact of the ARRIVE guidelines on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This Explanation and Elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2019, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature.As a new international working groupthe authors of this publication, we have revised the guidelines to update them and facilitate their uptake; the ARRIVE guidelines 2019 are published alongside this paper [13]. We have updated the recommendations in line with current best practice, reorganised the information and classified the items into two sets. The ARRIVE Essential 10 constitute the minimum reporting requirement and the Recommended Set provides further context to the study described. The two sets help authors, journal staff, editors and reviewers use the guidelines in practice, and allow a pragmatic implementation with an initial focus on the most critical issues. Once the Essential 10 are consistently reported in manuscripts, items from the Recommended Set can be added to journal requirements over time until all 21 items are routinely reported in all manuscripts. Full methodology for the revision and the allocation of items into sets is described in the accompanying publication [13].A key aspect of the revision was to develop this Explanation and Elaboration document to provide background and rationale for each of the 21 items of ARRIVE 2019. Here we present additional guidance for each item and subitem, explain the importance of reporting this information in manuscripts that describe animal research, elaborate on what to report, and provide supporting evidence. Each subitem is also illustrated with examples of good reporting from the published literature. Box 1: GlossaryBias: Introduction of a systematic error in the estimated effect of an intervention, caused by inadequacies in the design, conduct, or analysis of an experiment.Effect size: Quantitative measure that estimates the magnitude of differences between groups, or relationships between variables. Experimental unit:Biological entity subjected to an intervention independently of all other units, such that it is possible to assign any two experimental units to different t...

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“…Further evidence for the key role of SERCA2a in HFpEF is as follows: (1) cardiomyocyte-specific deletion of SERCA2a in mice (SERCA2a KO) caused diastolic HF94; and (2) SERCA2a gene therapy could reverse ageing-induced diastolic dysfunction7 and endothelial dysfunction,95 which are HFpEF-related risk factors. Therefore, it is possible that impaired SERCA2a function in HFpEF contributes to incomplete relaxation and is associated with other mechanisms, including endothelial dysfunction, inflammation and interstitial fibrosis.…”

Section: Serca2a As a Potential Target In Hfpef With Low Bnp Levelsmentioning

confidence: 99%

New insights into SERCA2a gene therapy in heart failure: pay attention to the negative effects of B-type natriuretic peptides

Zhai

Luo

et al. 2018

J Med Genet

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Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) is a target of interest in gene therapy for heart failure with reduced ejection fraction (HFrEF). However, the results of an important clinical study, the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, were controversial. Promising results were observed in the CUPID 1 trial, but the results of the CUPID 2 trial were negative. The factors that caused the controversial results remain unclear. Importantly, enrolled patients were required to have a higher plasma level of B-type natriuretic peptide (BNP) in the CUPID 2 trial. Moreover, BNP was shown to inhibit SERCA2a expression. Therefore, it is possible that high BNP levels interact with treatment effects of SERCA2a gene transfer and accordingly lead to negative results of CUPID 2 trial. From this point of view, effects of SERCA2a gene therapy should be explored in heart failure with preserved ejection fraction, which is characterised by lower BNP levels compared with HFrEF. In this review, we summarise the current knowledge of SERCA2a gene therapy for heart failure, analyse potential interaction between BNP levels and therapeutic effects of SERCA2a gene transfer and provide directions for future research to solve the identified problems.

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Sustained Toll-Like Receptor 9 Activation Promotes Systemic and Cardiac Inflammation, and Aggravates Diastolic Heart Failure in SERCA2a KO Mice

Cited by 13 publications

References 34 publications

Various aspects of inflammation in heart failure

Various aspects of inflammation in heart failure

Reporting animal research: Explanation and Elaboration for the ARRIVE guidelines 2019

New insights into SERCA2a gene therapy in heart failure: pay attention to the negative effects of B-type natriuretic peptides

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