scholarly journals The role of proinflammatory cytokines in the development of anthracycline-induced heart failure

2020 ◽  
Vol 35 (2) ◽  
pp. 66-74
Author(s):  
A. T. Teplyakov ◽  
S. N. Shilov ◽  
A. A. Popova ◽  
E. N. Berezikova ◽  
E. V. Grakova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Heart Failure ◽  
Proinflammatory Cytokines ◽  
Cardiac Injury ◽  
Cardiovascular Complications ◽  
Anthracycline Antibiotics ◽  
Anthracycline Therapy ◽  
Tnf Α ◽  
Group 1

Objective. To study the pathogenetic and prognostic role of cytokines (tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)) in the development of anthracycline-induced chronic heart failure (CHF).Material and Methods. A total of 176 women with breast cancer who received anthracycline antibiotics as a part of polychemotherapy regimens were examined. Upon examination, the patients in remission were divided into two groups within 12 months after the completion of chemotherapy: patients with the development of cardiotoxic remodeling (group 1, n = 52) and women with preserved cardiac function (group 2, n = 124). All patients received echocardiography study before, during, and after chemotherapy. Biochemical blood tests were done to determine the levels of TNF-α and IL-1β before chemotherapy, immediately after it, and 12 months after chemotherapy completion. Determination of polymorphisms of the TNF-α (–308G/A, rs1800629) and IL-1β genes (+3953, rs1143634) was carried out by polymerization chain reaction.Results. A higher level of TNF-α and IL-1β in group 1 was associated with the development of heart failure 12 months after the end of chemotherapy. The level of TNF-α over 7.5 pg/mL after the completion of chemotherapy allowed to predict the development of cardiovascular complications in women receiving anthracycline therapy with sensitivity of 44.2% and specificity of 75.8% (AUS = 0.600; 95% CI = 0.524–0.673; p = 0.035). The study did not reveal any significant differences in the frequency distribution for genotypes of 308G/A polymorphism (rs1800629) of the TNF-α gene and +3953 (rs1143634) polymorphism of the IL-1β gene in the studied groups.Conclusion. Patients with breast cancer who developed anthracycline-induced heart failure 12 months after the end of chemotherapy had the increased levels of TNF-α and IL-1β suggesting the pathogenetic role of proinflammatory cytokines in the development of cardiac injury during anthracycline therapy. 

Omentin-1 attenuates glucocorticoid-induced cardiac injury by phosphorylating GSK3β

2021 ◽  
Vol 66 (4) ◽  
pp. 273-283
Author(s):  
Zhousheng Jin ◽  
Fangfang Xia ◽  
Jiaojiao Dong ◽  
Tingting Lin ◽  
Yaoyao Cai ◽  
...  
Keyword(s):  
Side Effects ◽  
Cardiac Hypertrophy ◽  
Cardiac Injury ◽  
Experimental Studies ◽  
Chronic Administration ◽  
Cardiovascular Complications ◽  
Rat Serum ◽  
Cardiac Side Effects ◽  
Beneficial Effects

Glucocorticoid excess often causes a variety of cardiovascular complications, including hypertension, atherosclerosis, and cardiac hypertrophy. To abrogate its cardiac side effects, it is necessary to fully disclose the pathophysiological role of glucocorticoid in cardiac remodelling. Previous clinical and experimental studies have found that omentin-1, one of the adipokines, has beneficial effects in cardiovascular diseases, and is closely associated with metabolic disorders. However, there is no evidence to address the potential role of omentin-1 in glucocorticoid excess-induced cardiac injuries. To uncover the links, the present study utilized rat model with glucocorticoid-induced cardiac injuries and clinical patients with abnormal cardiac function. Chronic administration of glucocorticoid excess reduced rat serum omentin-1 concentration, which closely correlated with cardiac functional parameters. Intravenous administration of adeno-associated virus encoding omentin-1 upregulated the circulating omentin-1 level and attenuated glucocorticoid excess-induced cardiac hypertrophy and functional disorders. Overexpression of omentin-1 also improved cardiac mitochondrial function, including the reduction of lipid deposits, induction of mitochondrial biogenesis, and enhanced mitochondrial activities. Mechanistically, omentin-1 phosphorylated and activated the GSK3β pathway in the heart. From a study of 28 patients with Cushing’s syndrome and 23 healthy subjects, the plasma level of glucocorticoid was negatively correlated with omentin-1, and was positively associated with cardiac ejection fraction and fractional shortening. Collectively, the present study provided a novel role of omentin-1 in glucocorticoid excess-induced cardiac injuries and found that the omentin-1/GSK3β pathway was a potential therapeutic target in combating the side effects of glucocorticoid.

Abstract 507: Activation of the Classically Pro-Apoptotic Death Receptor 5 Promotes Physiological Hypertrophy and Cardiomyocyte Survival

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Toby Thomas ◽  
Miles Tanner ◽  
Laurel Grisanti
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cardiac Fibrosis ◽  
Death Receptor ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Death Receptor 5 ◽  
Tnf Α ◽  
Cardiomyocyte Survival

Heart failure is hallmarked by a combination of cardiomyocyte hypertrophy and death. Apoptosis, one of the primary mechanisms of cell death, occurs through finely tuned extrinsic or intrinsic pathways. Of the mediators involved in extrinsic apoptotic signaling, some have been extensively studied, such as tumor necrosis factor ((TNF)-α), while others have been relatively untouched. One such receptor is Death Receptor 5 (DR5) which, along with its ligand TNF-Related Apoptosis Inducing Ligand (TRAIL), have recently been implicated as a biomarker in determining the progression and outcome in patients following multiple heart failure etiologies, suggesting a novel role of DR5 signaling in the heart. These studies suggest a potentially protective role for DR5 in the heart; however, the function of TRAIL/DR5 in the heart has been virtually unstudied. Our goal was to explore the role of TRAIL/DR5 in cardiomyocyte hypertrophy and survival with the hypothesis that DR5 promotes cardiomyocyte survival and growth through non-canonical mechanisms. Mice treated with the DR5 agonist bioymifi or a DR5 agonist antibody, MD5-1, were absent of cell death, while an increase in hypertrophy was observed without a decline in cardiac function. In isolated cardiomyocytes, this pro-hypertrophic phenotype was determined to operate through MMP-dependent cleavage of HB-EGFR, leading to transactivation of EGFR and ERK1/2 signaling. To determine the role of DR5 in heart failure, a chronic catecholamine administration model was used and DR5 activation was found to decrease cardiomyocyte death and cardiac fibrosis. ERK1/2, a well characterized pro-survival, pro-hypertrophic kinase is activated in the heart with DR5 agonist administration and may represent the mechanistic link through which DR5 is imparting cardioprotection. In summary, DR5 activation promotes cardiomyocyte hypertrophy and survival and prevents cardiac fibrosis via a non-canonical MMP-EGFR-ERK1/2 pathway. Taken together, these studies identify a previously undetermined role for DR5 in the heart and identify novel therapeutic target for the treatment of heart failure.

HSP60 in heart failure: abnormal distribution and role in cardiac myocyte apoptosis

2007 ◽  
Vol 293 (4) ◽  
pp. H2238-H2247 ◽  
Author(s):  
Li Lin ◽  
S. C. Kim ◽  
Yin Wang ◽  
S. Gupta ◽  
B. Davis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Plasma Membrane ◽  
Cell Surface ◽  
Cardiac Myocyte ◽  
Cardiac Injury ◽  
Acute Injury ◽  
Tnf Α ◽  
Inflammatory State ◽  
Cardiac Myocyte Apoptosis ◽  
End Stage

Heat shock protein (HSP) 60 is a mitochondrial and cytosolic protein. Previously, we reported that HSP60 doubled in end-stage heart failure, even though levels of the protective HSP72 were unchanged. Furthermore, we observed that acute injury in adult cardiac myocytes resulted in movement of HSP60 to the plasma membrane. We hypothesized that the inflammatory state of heart failure would cause translocation of HSP60 to the plasma membrane and that this would provide a pathway for cardiac injury. Two models were used to test this hypothesis: 1) a rat model of heart failure and 2) human explanted failing hearts. We found that HSP60 localized to the plasma membrane and was also found in the plasma early in heart failure. Plasma membrane HSP60 localized to lipid rafts and was detectable on the cell surface with the use of both flow cytometry and confocal microscopy. Localization of HSP60 to the cell surface correlated with increased apoptosis. In heart failure, HSP60 is in the plasma membrane fraction, on the cell surface, and in the plasma. Membrane HSP60 correlated with increased apoptosis. Release of HSP60 may activate the innate immune system, promoting a proinflammatory state, including an increase in TNF-α. Thus abnormal trafficking of HSP60 to the cell surface may be an early trigger for myocyte loss and the progression of heart failure.

scholarly journals Acute Suppression of Circulating sCD40L During Hyperglycemia and Euglycemic-Hyperinsulinemia in Healthy Young Males

2008 ◽  
Vol 56 (7) ◽  
pp. 902-910 ◽  
Author(s):  
Stacy R. Oliver ◽  
Rebecca L. Flores ◽  
Andria M. Pontello ◽  
Jaime S. Rosa ◽  
Frank P. Zaldivar ◽  
...  
Keyword(s):  
Ketone Bodies ◽  
Cardiovascular Complications ◽  
Protective Role ◽  
Young Males ◽  
Tnf Superfamily ◽  
Blood Drawing ◽  
Tnf Α ◽  
Epidermal Growth ◽  
Glucose Lowering Effect

sCD40L is a proatherogenic cytokine, part of the tumor necrosis factor (TNF) superfamily and consistently associated with obesity, diabetes, and increased cardiovascular risk. Although the role of sCD40L in the onset/progression of cardiovascular complications of dysmetabolic diseases may be modulated by acute and/or chronic fluctuations of plasma insulin and glucose, very little has been done to clarify this interaction. The kinetic profile of sCD40L (and, in an exploratory manner, of several immunomodulatory factors), were measured during hyperglycemia and euglycemic-hyperinsulinemia in a group of 10 healthy young males (26.8 ± 1.4 years). After an overnight fast, intravenous (iv) catheters were placed in antecubital veins of both arms for blood drawing and dextrose/insulin iv infusions. Procedures lasted 240 minutes including baseline (t = 0-60), hyperglycemia (t = 60-150; plasma glucose ∼220 mg/dL via iv dextrose infusion), and euglycemic-hyperinsulinemia (t = 150-240; glucose infusion continued to clamp glycemic levels between 80 and 110 mg/dL; constant insulin infusion at 1.5 mU/kg/minute).Plasma for cytokine assays was sampled at 12 separate time-points. Plasma levels of sCD40L were significantly reduced (P < 0.01) during hyperglycemia and euglycemic-hyperinsulinemia, paralleling the kinetic profiles of free fatty acids and ketone bodies. This pattern was also observed in other immunomodulatory factors (notably cortisol and epidermal growth factor), while (interleukin [IL]-1α, IL-4, IL-6, IL-9, IL-10, TNF-α, Eotaxin) did not change significantly. Significant reductions of the proatherogenic cytokine sCD40L were observed during endogenous and exogenous hyperinsulinemia, independent of prevailing glucose concentration, in young healthy males. Our data suggest a mechanism by which correct insulin action may exert a beneficial protective role against inflammation, independent of its immediate glucose-lowering effect.

New insights into the pathological role of TNF-α in early cardiac dysfunction and subsequent heart failure after infarction in rats

2004 ◽  
Vol 287 (1) ◽  
pp. H340-H350 ◽  
Author(s):  
C. Berthonneche ◽  
T. Sulpice ◽  
F. Boucher ◽  
L. Gouraud ◽  
J. de Leiris ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Diastolic Pressure ◽  
Subsequent Development ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Direct Role ◽  
Volume Curve ◽  
Tnf Α

A marked increase in plasma TNF-α has been described in patients with chronic heart failure (CHF). Nevertheless, little is known about the direct role of this cytokine early after myocardial infarction (MI) and its possible effects on the subsequent development of CHF. Wistar rats were subjected to permanent in vivo coronary artery ligation. At 5, 7, and 9 days after MI, cardiac function, passive compliance of the left ventricle (LV), and cardiac geometry were evaluated. The same model was used to perform pharmacological studies 7 days and 10 wk after MI in rats treated with monomeric recombinant human soluble TNF-α receptor type II (sTNF-RII, 40 μg/kg iv) or a placebo on day 3. Maximal alterations of cardiac function and geometry occurred 7 days after MI, which correlated chronologically with a peak of cardiac and serum TNF-α, as shown by immunohistochemistry and ELISA, respectively. sTNF-RII improved LV end-diastolic pressure under basal conditions and after volume overload 7 days and 10 wk after MI. Moreover, a significant leftward shift of the pressure-volume curve in the sTNF-RII-treated group 7 days after MI indicated a preservation of LV volume. Infarct expansion index was also significantly improved by sTNF-RII 7 days after MI ( P < 0.01). Nevertheless, 10 wk after MI, geometric indexes and passive pressure-volume curves were not significantly improved by the treatment. In conclusion, TNF-α plays a major role in cardiac alterations 7 days after MI in rats and contributes to hemodynamic derangement, but not to cardiac remodeling, in subsequent CHF.

scholarly journals Use of Defined Mutants To Assess the Role of theCampylobacter rectus S-Layer in Bacterium-Epithelial Cell Interactions

2000 ◽  
Vol 68 (3) ◽  
pp. 1465-1473 ◽  
Author(s):  
Beinan Wang ◽  
Ellen Kraig ◽  
David Kolodrubetz
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Proinflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Periodontal Diseases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Minor Effect ◽  
Mrna Levels ◽  
Tnf Α

ABSTRACT Campylobacter rectus is a periodontal pathogen with a 150-kDa protein on its cell surface. This protein forms a paracrystalline lattice, called the S-layer, surrounding the outer membrane of this gram-negative bacterium. To initiate a genetic analysis of the possible role of the S-layer in the initial interaction of C. rectus with host epithelial cells, C. rectus strains lacking the S-layer protein gene (crsA) were constructed by allelic exchange mutagenesis. Surprisingly, the lack of the S-layer had only a minor effect on the interaction of C. rectus with HEp-2 epithelial cells; CrsA+ cells were 30 to 50% more adherent than were CrsA− bacteria. Since the host cell expression of cytokines appears to play an important role in the pathogenesis of periodontal diseases, the effect of the S-layer on the epithelial cell cytokine response was also examined by quantitative reverse transcriptase PCR and enzyme-linked immunosorbent assay. Although there were no changes in the mRNA levels for the anti-inflammatory cytokines interleukin-1 receptor agonist (IL-1ra), IL-13, and transforming growth factor β, the expression and secretion of the proinflammatory cytokines IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) were significantly induced by both wild-type C. rectus and CrsA− bacteria. Interestingly, the kinetics of cytokine induction differed for the CrsA+ and CrsA−bacteria. At early time points, the HEp-2 cells challenged with CrsA− bacteria produced higher levels of IL-6, IL-8, and TNF-α mRNA and protein than did cells challenged with CrsA+ bacteria. We conclude that C. rectus may help initiate periodontitis by increasing the expression of proinflammatory cytokines and that the S-layer may temper this response to facilitate the survival of C. rectus at the site of infection.

scholarly journals The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

2021 ◽  
Author(s):  
Nicholas W. Chavkin ◽  
Soichi Sano ◽  
Ying Wang ◽  
Kosei Oshima ◽  
Hayato Ogawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Planar Cell Polarity ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Orphan Receptor ◽  
Myofibroblast Differentiation ◽  
Cultured Fibroblasts

AbstractBackgroundA hallmark of heart failure is cardiac fibrosis, which results from the injury-induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early pro-inflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation.Methods and ResultsThe role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction (TAC) surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after TAC surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2-KO mice displayed a pro-inflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, TAC surgery led to the death of all mice by day 6 that was associated with myocardial hyper-inflammation and vascular leakage.ConclusionsTogether, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

scholarly journals The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

2021 ◽  
Author(s):  
Nicholas W. Chavkin ◽  
Soichi Sano ◽  
Ying Wang ◽  
Kosei Oshima ◽  
Hayato Ogawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Orphan Receptor ◽  
Myofibroblast Differentiation ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Cultured Fibroblasts

Background A hallmark of heart failure is cardiac fibrosis, which results from the injury‐induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early proinflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase–like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and Results The role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after transverse aortic constriction surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2 knockout mice displayed a proinflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, transverse aortic constriction surgery led to the death of all mice by day 6 that was associated with myocardial hyperinflammation and vascular leakage. Conclusions Together, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

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