Cardiac fibroblasts: contributory role in septic cardiac dysfunction

Tomita, Kengo; Takashina, Mitchinori; Mizuno, Natsumi; Sakata, Kei; Hattori, Kohshi; Imura, Johji; Ohashi, Wakana; Hattori, Yoshiyuki

doi:10.1016/j.jss.2014.09.012

Cited by 36 publications

(22 citation statements)

References 38 publications

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“…Brown et al observed similar microlesions in the heart of Streptococcus pneumonia –infected mice and sepsis patients, suggesting that this is a characteristic phenomenon of cardiac damage during bacterial sepsis. Notably, Ft.n infection in mice causes cardiac interstitial and perivascular fibrosis (Figure S1), a general pathological condition associated with chronic inflammation found in the cecal ligation and puncture (CLP)‐induced sepsis model . Importantly, histological analysis of microlesions in the Ft.n ‐infected heart tissue reveals the absence of immune cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, Ft.n infection in mice causes cardiac interstitial and perivascular fibrosis ( Figure S1), a general pathological condition associated with chronic inflammation found in the cecal ligation and puncture (CLP)induced sepsis model. 44 Importantly, histological analysis of microlesions in the Ft.n-infected heart tissue reveals the absence of immune cell infiltration. In contrast, we observed robust infiltration of immune cells in the posterior region and myocardium of the heart (Figure 7), suggesting that the Ft.n infection causes cardiac inflammation and damage.…”

Section: Discussionmentioning

confidence: 99%

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Cardiac Electrical and Structural Changes During Bacterial Infection: An Instructive Model to Study Cardiac Dysfunction in Sepsis

Makara

Hoang

Ganesan

et al. 2016

JAHA

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BackgroundSepsis patients with cardiac dysfunction have significantly higher mortality. Although several pathways are associated with myocardial damage in sepsis, the precise cause(s) remains unclear and treatment options are limited. This study was designed to develop a new model to investigate the early events of cardiac damage during sepsis progression.Methods and Results Francisella tularensis subspecies novicida (Ft.n) is a Gram‐negative intracellular pathogen causing severe sepsis syndrome in mice. BALB/c mice (N=12) were sham treated or infected with Ft.n through the intranasal route. Serial electrocardiograms were recorded at multiple time points until 96 hours. Hearts were then harvested for histology and gene expression studies. Similar to septic patients, we illustrate both cardiac electrical and structural phenotypes in our murine Ft.n infection model, including prominent R' wave formation, prolonged QRS intervals, and significant left ventricular dysfunction. Notably, in infected animals, we detected numerous microlesions in the myocardium, previously observed following nosocomial Streptococcus infection and in sepsis patients. We show that Ft.n‐mediated microlesions are attributed to cardiomyocyte apoptosis, increased immune cell infiltration, and expression of inflammatory mediators (tumor necrosis factor, interleukin [IL]‐1β, IL‐8, and superoxide dismutase 2). Finally, we identify increased expression of microRNA‐155 and rapid degradation of heat shock factor 1 following cardiac Ft.n infection as a primary cause of myocardial inflammation and apoptosis.ConclusionsWe have developed and characterized an Ft.n infection model to understand the pathogenesis of cardiac dysregulation in sepsis. Our findings illustrate novel in vivo phenotypes underlying cardiac dysfunction during Ft.n infection with significant translational impact on our understanding of sepsis pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cardiac Electrical and Structural Changes During Bacterial Infection: An Instructive Model to Study Cardiac Dysfunction in Sepsis

Makara

Hoang

Ganesan

et al. 2016

JAHA

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“…While the cardiac fibroblast serves a baseline homeostasis role or transforms to an activated myofibroblast in response to injury, intermediary phenotypes exist, and fibroblasts display a range of phenotypes in response to individual in vitro stimuli [1, 61]. For example, cardiac fibroblasts stimulated with lipopolysaccharide show increased pro-inflammatory cytokine production and decreased collagen synthesis [37, 59]. Fibroblasts stimulated with transforming growth factor (TGF)β1 increase collagen synthesis and differentiate to a myofibroblast phenotype [62, 65].…”

Section: Introductionmentioning

confidence: 99%

Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis

et al. 2019

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Cardiac fibroblasts are the major producers of extracellular matrix (ECM) to form infarct scar. We hypothesized that fibroblasts undergo a spectrum of phenotype states over the course of myocardial infarction (MI) from early onset to scar formation. Fibroblasts were isolated from the infarct region of C57BL/6J male mice (3–6 months old, n = 60) at days 0 (no MI control) and 1, 3, or 7 after MI. Whole transcriptome analysis was performed by RNA-sequencing. Of the genes sequenced, 3371 were differentially expressed after MI. Enrichment analysis revealed that MI day 1 fibroblasts displayed pro-inflammatory, leukocyte-recruiting, pro-survival, and anti-migratory phenotype through Tnfrsf9 and CD137 signaling. MI day 3 fibroblasts had a proliferative, pro-fibrotic, and pro-angiogenic profile with elevated Il4ra signaling. MI day 7 fibroblasts showed an anti-angiogenic homeostatic-like myofibroblast profile and with a step-wise increase in Acta2 expression. MI day 7 fibroblasts relied on Pik3r3 signaling to mediate Tgfb1 effects and Fgfr2 to regulate PI3K signaling. In vitro, the day 3 MI fibroblast secretome stimulated angiogenesis, while day 7 MI fibroblast secretome repressed angiogenesis through Thbs1 signaling. Our results reveal novel mechanisms for fibroblasts in expressing pro-inflammatory molecules and regulating angiogenesis following MI.Electronic supplementary materialThe online version of this article (10.1007/s00395-019-0715-4) contains supplementary material, which is available to authorized users.

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“…Importantly, ACE, an important component of renin–angiotensin system (RAS) encoded by ACE gene, is known to exert a crucial role in regulating blood pressure [30]. Cardiac dysfunction, a severe and frequent complication of SS, results in the high mortality rate of sepsis [31]. Along with sepsis, it is in close association with inflammation as well as declined fatty acid oxidation [32].…”

Section: Discussionmentioning

confidence: 99%

Correlations between ACE single nucleotide polymorphisms and prognosis of patients with septic shock

et al. 2017

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The aim of the present study is to investigate association between septic shock (SS) and angiotensin I-converting enzyme (ACE) single nucleotide polymorphisms (SNPs). From October 2009 to December 2016, 238 SS patients and 242 healthy individuals were selected for our study. ACE activity was detected, ACE rs4291 and rs4646994 polymorphisms were detected using PCR-restriction fragment length polymorphism (PCR-RFLP). The Kaplan–Meier survival curve was employed to evaluate the association between ACE SNPs and patients’ survival and univariate and multivariate analyses to estimate risk factors for SS. ACE activity in the case group was increased in comparison with the control group. Allele and genotype frequencies of rs4291 and rs4646994 were different between the case and control groups. The TT genotype frequency of the rs4291 polymorphisms and the DD genotype of the rs4646994 polymorphisms of the case group were higher than those in the control group. The AT and TT genotypes indicated a significant elevation of ACE activity than the AA genotype, while a significant decline was found in the DI and II genotypes in comparison with the DI genotype. Patients with TT or DD genotypes had increased fatality rate within 7 and 30 days when compared with those with non-TT or non-DD genotypes. Lower sepsis-related organ failure assessment (SOFA) scores, rs4291, serum ACE and rs4646994 were all considered as risky factors for SS patients. The study demonstrates that TT genotype of rs4291 or DD genotype of rs4646994 may be indicative of a higher risk of SS and a poorer prognosis in SS patients.

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Cardiac fibroblasts: contributory role in septic cardiac dysfunction

Cited by 36 publications

References 38 publications

Cardiac Electrical and Structural Changes During Bacterial Infection: An Instructive Model to Study Cardiac Dysfunction in Sepsis

Cardiac Electrical and Structural Changes During Bacterial Infection: An Instructive Model to Study Cardiac Dysfunction in Sepsis

Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis

Correlations between ACE single nucleotide polymorphisms and prognosis of patients with septic shock

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