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 Immune Cells and Immunotherapy for Cardiac Injury and Repair

2021 ◽  
Vol 128 (11) ◽  
pp. 1766-1779
Author(s):  
Joel G. Rurik ◽  
Haig Aghajanian ◽  
Jonathan A. Epstein
Keyword(s):  
Heart Failure ◽  
Immune Cells ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Cardiac Injury ◽  
Therapeutic Interventions ◽  
Acute Injury ◽  
Myocyte Function ◽  
New Treatment ◽  
Injury And Repair

Cardiac injury remains a major cause of morbidity and mortality worldwide. Despite significant advances, a full understanding of why the heart fails to fully recover function after acute injury, and why progressive heart failure frequently ensues, remains elusive. No therapeutics, short of heart transplantation, have emerged to reliably halt or reverse the inexorable progression of heart failure in the majority of patients once it has become clinically evident. To date, most pharmacological interventions have focused on modifying hemodynamics (reducing afterload, controlling blood pressure and blood volume) or on modifying cardiac myocyte function. However, important contributions of the immune system to normal cardiac function and the response to injury have recently emerged as exciting areas of investigation. Therapeutic interventions aimed at harnessing the power of immune cells hold promise for new treatment avenues for cardiac disease. Here, we review the immune response to heart injury, its contribution to cardiac fibrosis, and the potential of immune modifying therapies to affect cardiac repair.

scholarly journals Intravenous iron therapy and circulating biomarkers of inflammation in men with heart failure with reduced ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Drozd ◽  
M Tkaczyszyn ◽  
K Wegrzynowska-Teodorczyk ◽  
M Kasztura ◽  
M Dziegala ◽  
...  
Keyword(s):  
Heart Failure ◽  
Intravenous Iron ◽  
Inflammatory Biomarkers ◽  
Iron Therapy ◽  
Reduced Ejection Fraction ◽  
Tnf Α ◽  
Inflammatory State ◽  
Iv Iron ◽  
Hs Crp ◽  
Intravenous Iron Therapy

Abstract Background Large randomized clinical trials have demonstrated that intravenous (IV) iron therapy in iron-deficient patients with heart failure with reduced ejection fraction (HFrEF) brings clinical benefits related to symptoms of the disease and exercise capacity. Mechanisms underlying beneficial effects of such repletion are still the subject of interest as this is not solely related to improved haematopoiesis (IV iron works also in non-anaemic subjects). In patients with chronic heart failure iron deficiency (ID) is linked with inflammatory processess but data regarding the impact of IV iron on inflammation is scarce. Purposes We evaluated whether IV iron therapy affects circulating biomarkers of pro-inflammatory state in men with HFrEF and concomitant ID. Methods This is the sub-analysis of the study to investigate the effects of IV ferric carboxymaltose (FCM) on the functioning of skeletal muscles in men with HFrEF. For the purposes of current research we analyzed data of 20 men with HFrEF (median age 68 (62, 75 – in brackets interquartile ranges, respectively) years, LVEF: 30 (25, 35) %, ischaemic HF aetiology: 85%, NYHA class I/II/III: 30%/50%/20%) and ID (definition according to ESC guidelines - ferritin <100 ng/mL, or ferritin 100–299 ng/mL with transferrin saturation [TSAT] <20%) who were randomized in a 1:1 ratio to receive either the 24-week therapy with IV FCM (dosing scheme as in the CONFIRM-HF trial) or saline (controls). The study was double-blinded. We used ELISA to evaluate different circulating pro-inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], tumor necrosis factor alpha [TNF-α], interleukin 6 [IL-6], interleukin 1 beta [IL-1β], interleukin 22 [IL-22]) at baseline and week 24. Results IV FCM therapy repleted iron stores in men with HFrEF as reflected by an increase in serum ferritin and TSAT, which was not seen in a control group. IV FCM therapy (as well as the saline administration) affected neither haemoglobin concentration nor parameters reflecting iron stores in red cells. Baseline serum ferritin was not related to hs-CRP, TNF-α, IL-6, IL-1β, and IL-22 (all p>0.23). Baseline TSAT was related to hs-CRP (r=−0.47, p=0.02) but not other inflammatory biomarkers. Levels of hs-CRP, TNF-α, IL-6, IL-1β, and IL-22 at week 0 were similar in subjects who received IV iron and controls (all p>0.22). Change from week 0 to week 24 adjusted for baseline value (delta W24-W0 as the percentage of W0) regarding IL-22 was lower in an active treatment arm as compared with saline (p=0.049) and there was a trend towards lower delta TNF-α in FCM group compared to saline (p=0.067). These findings were not valid for other measured pro-inflammatory biomarkers. Conclusions In men with HFrEF and concomitant ID intravenous iron therapy with FCM affects biomarkers of pro-inflammatory state. Clinical relevance of this finding requires further translational research. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This research was funded by the National Science Centre (Poland) grant allocated on the basis of the decision number DEC-2012/05/E/NZ5/00590

scholarly journals A mechanistic role for cardiac myocyte apoptosis in heart failure

2003 ◽  
Vol 111 (10) ◽  
pp. 1497-1504 ◽  
Author(s):  
Detlef Wencker ◽  
Madhulika Chandra ◽  
Khanh Nguyen ◽  
Wenfeng Miao ◽  
Stavros Garantziotis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis

Upregulation of GRP78 and caspase-12 in diastolic failing heart.

2008 ◽  
Vol 55 (3) ◽  
pp. 511-516 ◽  
Author(s):  
Yingying Sun ◽  
Guanghui Liu ◽  
Tao Song ◽  
Fang Liu ◽  
Weiqiang Kang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Diastolic Heart Failure ◽  
Critical Role ◽  
Mrna Levels ◽  
Apoptotic Pathway ◽  
Spontaneously Hypertensive ◽  
Caspase 12 ◽  
Apoptosis Pathways ◽  
Cardiac Myocyte Apoptosis

The endoplasmic reticulum (ER) fulfills multiple cellular functions. Various stimuli can potentially cause ER stress (ERS). ERS is one of the intrinsic apoptosis pathways and apoptosis plays a critical role in hypertension. Glucose regulated protein 78 (GRP78) has been widely used as a marker for ERS and caspase-12 mediated apoptosis was a specific apoptotic pathway of ER. The expression of GRP78 and caspase-12 remains poorly understood in the diastolic heart failure resulting from hypertension. We used spontaneously hypertensive rats (SHRs) to establish a model of diastolic heart failure, and performed immunohistochemistry, western blot, and real-time PCR to analyze GRP78 and caspase-12. We found that GRP78 and caspase-12 had enhanced expression at protein and mRNA levels. These results suggest that GRP78 and caspase-12 were upregulated in cardiomyocytes and ERS can contribute to cardiac myocyte apoptosis in the diastolic heart failure resulting from hypertension.

In vitro endothelial cell activation and inflammatory responses in end-stage heart failure

2006 ◽  
Vol 101 (5) ◽  
pp. 1466-1473 ◽  
Author(s):  
Ginette S. Hoare ◽  
Emma J. Birks ◽  
Christopher Bowles ◽  
Nandor Marczin ◽  
Magdi H. Yacoub
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Activation ◽  
Endothelial Cell Activation ◽  
Tnf Α ◽  
Patients With Heart Failure ◽  
End Stage Heart Failure ◽  
End Stage ◽  
Iκbα Degradation

Background: vascular endothelial cell activation and dysfunction are observed in patients with severe heart failure and may contribute to systemic manifestations of this syndrome. It remains unknown whether inflammatory activation of these cells occurs in these patients because of increased circulating proinflammatory mediators. Aim: to determine whether the serum from patients with heart failure possesses a net proinflammatory bioactivity to active proinflammatory pathways in cultured endothelial cells. Methods: serum was obtained from stable patients with end-stage heart failure undergoing elective cardiac transplantation (Tx) and severely decompensated patients with heart failure requiring emergency left ventricular assist device (LVAD) implantation. Net proinflammatory bioactivity of serum was investigated by monitoring IκBα degradation and E-selectin expression in cultured human pulmonary artery endothelial cells (HPAEC) following incubation with serum samples. Serum cytokine concentrations were measured by ELISA and neutralizing antibodies were used to determine the role of specific factors in the observed bioactivity. Result: serum from both patient groups induced HPAEC IκBα degradation. Low basal HPAEC E-selectin expression significantly increased following treatment with Tx but not LVAD serum. Serum tumor necrosis factor-α (TNF-α) and IL-10 concentrations were higher in patients with LVAD than those with Tx, and soluble TNF-α receptor expression was high in both groups. Neither TNF-α nor IL-10 blocking experiments altered either bioassay result. Conclusion: activation of a specific profile of pro- and anti-inflammatory mediators is associated with heart failure resulting in HPAEC nuclear factor (NF)-κB activation. However, E-selectin expression is further regulated by unidentified factors. TNF-α is upregulated but appears to play no part in NFκB activation in these patients. These findings could have important therapeutic implications.

p38 and ERK1/2 MAPKs mediate the interplay of TNF-α and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis

2007 ◽  
Vol 293 (6) ◽  
pp. H3524-H3531 ◽  
Author(s):  
Sanjiv Dhingra ◽  
Anita K. Sharma ◽  
Dinender K. Singla ◽  
Pawan K. Singal
Keyword(s):  
Oxidative Stress ◽  
P38 Mapk ◽  
Cardiac Myocyte ◽  
Cell Injury ◽  
Male Rats ◽  
Tnf Α ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis ◽  
Induced Changes

It is known that TNF-α increases the production of ROS and decreases antioxidant enzymes, resulting in an increase in oxidative stress. IL-10 appears to modulate these effects. The present study investigated the role of p38 and ERK1/2 MAPKs in mediating the interplay of TNF-α and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis in Sprague-Dawley male rats. Isolated adult cardiac myocytes were exposed to TNF-α (10 ng/ml), IL-10 (10 ng/ml), and IL-10 + TNF-α ( ratio 1) for 4 h. H2O2(100 μM) as a positive control and the antioxidant Trolox (20 μmol/l) were used to confirm the involvement of oxidative stress. H2O2treatment increased oxidative stress and apoptosis; TNF-α mimicked these effects. Exposure to TNF-α significantly increased ROS production, caused cell injury, and increased the number of apoptotic cells and Bax-to-Bcl-xl ratio. This change was associated with an increase in the phospho-p38 MAPK-to-total p38 MAPK ratio and a decrease in the phospho-ERK1/2-to-total ERK1/2 ratio. IL-10 treatment by itself had no effect on these parameters, but it prevented the above-listed changes caused by TNF-α. The antioxidant Trolox modulated TNF-α-induced changes in Bax/Bcl-xl, cell injury, and MAPKs. Preexposure of cells to the p38 MAPK inhibitor SB-203580 prevented TNF-α-induced changes. Inhibition of the ERK pathway with PD-98059 attenuated the protective role of IL-10 against TNF-α-induced apoptosis. This study provides evidence in support of the essential role of p38 and ERK1/2 MAPKs in the interactive role of TNF-α and IL-10 in cardiac myocyte apoptosis.

Burn plasma mediates cardiac myocyte apoptosis via endotoxin

2002 ◽  
Vol 282 (5) ◽  
pp. H1907-H1914 ◽  
Author(s):  
Deborah L. Carlson ◽  
Ellis Lightfoot ◽  
Debora D. Bryant ◽  
Sandra B. Haudek ◽  
David Maass ◽  
...  
Keyword(s):  
Primary Culture ◽  
Caspase 3 ◽  
Cardiac Myocyte ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tnf Α ◽  
Apoptotic Effect ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis ◽  
Factor Α

Thermal trauma is associated with cardiac myocyte apoptosis in vivo. To determine whether cardiac myocyte apoptosis could be secondary to burn-induced cytokines or inflammatory mediators, we investigated the effects of tumor necrosis factor-α (TNF-α) and burn plasma on a murine cardiac myocyte cell line and primary culture myocytes. HL-1 cells were exposed to plasma isolated from burned or sham rats. Burn, but not sham plasma, induced significant increases in caspase-3 activity and DNA fragmentation. Similar results were obtained in primary culture rat myocytes. A dose-dependent increase in caspase-3 activity was observed when HL-1 cells were incubated with increasing concentrations of TNF-α. Even though TNF-α increased apoptosis, enzyme-linked immunosorbent assay detected no TNF-α in burn plasma. Burn plasma also failed to induce TNF-α mRNA, eliminating an autocrine mechanism of TNF-α secretion and binding. Also, treatment of burn plasma containing rhuTNFR:Fc failed to inhibit apoptosis. To examine the possibility that endotoxin within burn plasma might account for the apoptotic effect, burn plasma was preincubated with rBPI21. Caspase-3 activity was reduced to control levels. These data indicate that burn plasma induces apoptosis in cardiac myocytes via an endotoxin-dependent mechanism and suggest that systemic inhibition of endotoxin may provide a therapeutic approach for treatment of burn-associated cardiac dysfunction.

scholarly journals Macrophages modulate cardiac function in lipotoxic cardiomyopathy

2012 ◽  
Vol 303 (11) ◽  
pp. H1366-H1373 ◽  
Author(s):  
Joel D. Schilling ◽  
Heather M. Machkovech ◽  
Alfred H. J. Kim ◽  
Reto Schwedwener ◽  
Jean E. Schaffer
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Myocyte ◽  
Cardiac Injury ◽  
Transgenic Mouse Model ◽  
Obesity And Diabetes ◽  
Increased Risk ◽  
Inflammatory Activation ◽  
Lipotoxic Cardiomyopathy

Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the α-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes.

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. 

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