endothelin-1 and Myocarditis

Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic volume overload secondary to aortocaval fistula and mitral regurgitation. Accordingly, mast cells have been implicated to have a major role in the pathophysiology of these cardiovascular disorders. In vitro studies have verified that mast cell proteases are capable of activating collagenase, gelatinases and stromelysin. Recent results have shown that with chronic ventricular volume overload, there is an elevation in mast cell density, which is associated with a concomitant increase in matrix metalloproteinase (MMP) activity and extracellular matrix degradation. However, the role of the cardiac mast cell is not one dimensional, with evidence from hypertension and cardiac transplantation studies suggesting that they can also assume a pro-fibrotic phenotype in the heart. These adverse events do not occur in mast cell deficient rodents or when cardiac mast cells are pharmacologically prevented from degranulating. This review is focused on the regulation and dual roles of cardiac mast cells in: (i) activating MMPs and causing myocardial fibrillar collagen degradation and (ii) causing fibrosis in the stressed, injured or diseased heart. Moreover, there is strong evidence that premenopausal female cardioprotection may at least partly be due to gender differences in cardiac mast cells. This too will be addressed.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Cell Differentiation; Cell Proliferation; Complement C5a; Endothelin-1; Female; Heart Failure; Heart Transplantation; Hematopoietic Stem Cells; Humans; Hypertension; In Vitro Techniques; Male; Mast Cells; Myocardial Infarction; Myocardial Reperfusion Injury; Myocarditis; Neuropeptides; Reactive Oxygen Species; Sex Characteristics; Ventricular Remodeling

The seriousness of scorpion envenomation results essentially from left cardiac function with pulmonary oedema and/or a state of shock. Adrenergic myocarditis, toxic myocarditis and myocardial ischemia are the 3 mechanisms that explain the cardiac dysfunction. Myocardial ischemia is not only due to the release of catecolamines but also the effect of the cytokines and/or neuropeptide Y on the coronary vessels. The cardiac damage can be due or enhanced by the depressive effect of the cytokines on the myocardial cells. The frequently observed hyperglycaemia only enhances the state of the already damaged myocardium.

Topics: Acidosis; Animals; beta-Thromboglobulin; Blood Platelets; Catecholamines; Cytokines; Endothelin-1; Humans; Hyperglycemia; Myocardial Ischemia; Myocarditis; Myocardium; Neuropeptide Y; Pulmonary Edema; Scorpion Stings; Scorpion Venoms; Scorpions; Shock, Cardiogenic; Stress, Physiological

Endothelin-1 has emerged as an important participant in the pathophysiology of a variety of cardiovascular diseases, where it may act on endocrine, paracrine and autocrine bases. Here we review its regulated biosynthesis, receptor-mediated signaling, and functional consequences in the heart, with particular emphasis on cardiac development and disease. Exploring published data employing molecular genetic mouse models of endothelin dysregulation, we highlight its heretofore underappreciated role as a pro-inflammatory cytokine. We also present novel micro-array data from one such mouse model, which implicate the specific downstream pathways that may mediate endothelin-1's effects.

Topics: Animals; Cardiomyopathies; Endothelin-1; Gene Expression Regulation; Humans; Myocarditis; Myocardium; Signal Transduction

Trypanosoma cruzi triggers a progressive myocarditis in mammalians through activation and recruitment of leukocytes and release of inflammatory mediators. The chemokine CX3CL1 has been highlighted for its potential role in the parasite controlling in end-pathological status of infected hosts. This study investigated the systemic and cardiac release of CX3CL1 in experimental T. cruzi infection and how this chemokine correlates with endothelin-1 and TNF. Male Fisher rats (n = 20) were infected, or not, by the Y strain of T. cruzi and parasitemia was daily evaluated and immunoassays performed in the cardiac tissue macerated supernatant and in serum to evaluate CX3CL1, endothelin, and TNF production on days 5 and 15 of infection. T. cruzi infection induced a higher serum and cardiac production of these mediators on days 5 and 15 of infection. In both periods of infection, respectively, CX3CL1 showed a positive correlation with TNF (r = 0.833, p < 0.001 and r = 0.723, p < 0.001) and endothelin-1 (r = 0.801, p < 0.05 and r = 0.857, p < 0.001), which reinforce its participation in the T. cruzi-induced myocarditis development.

Topics: Animals; Chagas Disease; Chemokine CX3CL1; Endothelin-1; Male; Myocarditis; Rats; Trypanosoma cruzi

Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Experimental autoimmune myocarditis (EAM) is a mouse model of post-infectious myocarditis and inflammatory cardiomyopathy. The pathological role of endothelin (ET) in myocarditis has not been elucidated.. EAM was induced by immunization of cardiac myosin peptide with complete Freund's adjuvant on days 0 and 7 in BALB/c mice. An ETA/ETB dual receptor antagonist, SB209670, was administered by a continuous infusion from a subcutaneous pump for 2 weeks.. An increase in the heart-to-body weight ratio was observed in SB209670-treated mice compared with vehicle-treated mice. Heart pathology in SB209670-treated mice was remarkable for gross inflammatory infiltration, in contrast to the lesser inflammation in the hearts of vehicle-treated mice. We found that an ET blockade decreased the number of Foxp3(+) regulatory T cells in the heart. The ET blockade also inhibited the expression of the suppressor of cytokine signaling 3 that plays a key role in the negative regulation of both Toll-like receptor- and cytokine receptor-mediated signaling. EAM is a CD4(+) T cell-mediated disease. CD4(+) T cells isolated from SB209670-treated EAM mice produced less IL-10 and more inflammatory cytokines, IL-6 and IL-17, than those isolated from vehicle-treated mice.. The ET receptor antagonist exacerbated autoimmune myocarditis in mice. Our novel findings suggest that ET may play an important role in the regulation of inflammation in myocarditis.

Topics: Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cell Differentiation; Chemokines; Disease Progression; Endothelin Receptor Antagonists; Endothelin-1; Flow Cytometry; Gene Expression Regulation; Lymph Nodes; Mice, Inbred BALB C; Myocarditis; Myocardium; Myosins; Receptor, Endothelin A; Receptor, Endothelin B; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Exposure to high altitude is a well-known environmental stress with physiological and metabolic consequences, with the major stressor being hypobaric hypoxia. The disruption in cellular homeostasis elicits several acute and chronic adaptations designed to diminish the stress imposed by the hypoxic insult. Highly conserved cellular machinery protects the myocardium from damage under reduced oxygen tension. In the present study, adult Sprague-Dawley rats were exposed to an altitude of 9754 m in a decompression chamber and screened on the basis of the time taken for onset of gasping. The animals were grouped as susceptible (<10 min), normal (10-25 min), and tolerant (>25 min). Histologically, susceptible animals showed increased myocardial inflammation and infiltration and greater CK-MB activity. These animals showed a three-fold increase in reactive oxygen species levels and subsequent oxidative damage to proteins and lipids as compared to control unexposed group. In tolerant animals, the damage was minimal. The resistance to damage in these animals was possibly due to enhanced myocardial antioxidant enzymes, catalase and superoxide dismutase. A significantly higher expression of HIF-1α and its responsive genes, including EPO, HO-1, and GLUT1, was seen in tolerant animals, although VEGF expression was enhanced in the susceptible group. Cytoprotective chaperones, HSP70 and HSP90, were elevated in the tolerant animals. The differential expression of these hypoxia-responsive molecules may thus act as potential biochemical markers for screening and identifying individuals susceptible to environmental stress.

Topics: Altitude; Animals; Atmospheric Pressure; Catalase; Creatine Kinase, MB Form; Dyspnea; Endothelin-1; Erythropoietin; Heme Oxygenase-1; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Malondialdehyde; Myocarditis; Myocardium; Nitric Oxide; Oxidative Stress; Protein Carbonylation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor A

In order to test the hypothesis that treatment with quercetin at a dose of 10 mg/kg protects from the progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy (DCM), we have used the rat model of EAM induced by porcine cardiac myosin. Our results identified that the post-myocarditis rats suffered from elevated endoplasmic reticulum (ER) stress and adverse cardiac remodelling in the form of myocardial fibrosis, whereas the rats treated with quercetin have been protected from these changes as evidenced by the decreased myocardial levels of ER stress and fibrosis markers when compared with the vehicle-treated DCM rats. In addition, the myocardial dimensions and cardiac function were preserved significantly in the quercetin-treated rats in comparison with the DCM rats treated with vehicle alone. Interestingly, the rats treated with quercetin showed significant suppression of the myocardial endothelin-1 and also the mitogen activated protein kinases (MAPK) suggesting that the protection offered by quercetin treatment against progression of EAM involves the modulation of MAPK signalling cascade. Collectively, the present study provides data to support the role of quercetin in protecting the hearts of the rats with post myocarditis DCM.

Topics: Animals; Apoptosis; Autoimmune Diseases; Biomarkers; Cardiac Myosins; Cardiotonic Agents; Cytochromes c; Endoplasmic Reticulum Stress; Endothelin-1; Fibrosis; Heart; Male; MAP Kinase Signaling System; Myocarditis; Myocardium; Organ Size; Osteopontin; Oxidative Stress; Quercetin; Rats; Rats, Inbred Lew; Ventricular Remodeling

Epidemiological studies suggest that NO₂ inhalation is associated with adverse effects on heart-related health, however, existing experimental data lack relevant evidences. In this study, a role for oxidative stress, endothelial dysfunction and inflammatory responses in the heart of rats treated with different concentrations of NO₂ (0, 5, 10 and 20 mg m⁻³) was investigated. Mild heart pathology occurred after 7-d exposure (6 h d⁻¹). Marked oxidative stress were induced as evaluated by reduction/induction of antioxidants (Cu/Zn-SOD, Mn-SOD and GPx) activity and increasing formation of MDA and PCO. Also, mRNA and protein biomarkers of vasoconstriction (ET-1, eNOS) and inflammation (TNF-α, IL-1β and ICAM-1) were up-regulated, and p53 mRNA expression, bax/bcl-2 ratio and the mean number of TUNEL-positive myocytes were increased as well. All the results implicate that NO₂ exerted injuries to mammals' heart, and the damage mechanisms were possibly associated with oxidative stress, endothelial dysfunction and inflammation.

Topics: Air Pollutants; Animals; Apoptosis; Biomarkers; Cytokines; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Heart; Inhalation Exposure; Male; Myocarditis; Myocytes, Cardiac; Nitrogen Dioxide; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase

Chagas' disease caused by the parasite, Trypanosoma cruzi, is accompanied by an acute myocarditis which can be fatal. Mice (A/J strain) infected with T. cruzi (Tulahuen strain) develop an acute myocarditis associated with high parasitemia and uniform mortality. Examination of the myocardium demonstrated myonecrosis, vasculitis and parasite pseudocysts. Immunoblot analysis and quantitative real time PCR of heart lysates demonstrated an increased expression of cell cycle regulatory proteins such as cyclins B1, D1, A1 and E1 and an increased expression of cdk2 when compared with uninfected controls. Extracellular signal-regulated kinase (ERK) was activated. Proliferating cell nuclear antigen (PCNA), endothelin-1, endothelin receptor type A (ET(A)) and endothelin receptor type B (ET(B)) expression were increased. Caveolin-1 is important in the regulation of ERK and cyclin D1. The expression of caveolin-1 as well as caveolin-2 and caveolin-3 was reduced. These data suggest that acute fatal T. cruzi myocarditis is accompanied by changes in cell cycle proteins such as the cyclins and caveolin and that the upregulation of the endothelin pathway may be important in the myocardial abnormalities and mortality observed in this mouse model.

Topics: Acute Disease; Animals; Caveolin 1; Chagas Disease; Cyclins; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Male; Mice; Myocarditis; RNA, Messenger; Trypanosoma cruzi

The mechanisms of coronary artery dysfunction in coxsackievirus B3 (CVB3)-mediated viral myocarditis are poorly understood. We used pressure myography of mouse septal coronary arteries to determine the early and late effects of CVB3 infection on vascular function. Male CD-1 mice (age 6-7 weeks) were infected with CVB3 (1.75 x 10(10) pfu, i.p.). Control mice were injected with PBS. Mice were killed at 3, 7, and 42 days post infection, and the ventricular septal artery was dissected and mounted on a pressure myograph. Pressure-induced myogenic tone was similar in CVB3-infected and sham-infected mice at 3 and 7 days post infection. However, at 42 days post infection constriction of septal arteries to pressures equal to or less than 60 mm Hg was enhanced in CVB3-infected mice compared with sham controls. Agonist-induced vasodilation, as assessed by response to acetylcholine (1 nM-3 microM), was unaltered at early time points (days 3 and 7) in CVB3-infected mice. At later time points (day 42), there was a significant decrease in ACh-induced vasodilation in CVB3-infected mice. Bosentan, an ET-1 (ETA and ETB) receptor antagonist, did not completely ameliorate the reduced ACh-induced vasodilation in 42-day infected mice, indicating that ET-1 does not contribute to vascular dysfunction. Smooth muscle function, as measured by constriction to KCl or dilation to sodium nitroprusside, was unchanged in infected mice at early and late time points. Immunohistochemistry and ET-1 immunoassay were then performed to assess ET-1 levels in CVB3- and sham-infected hearts. There were no differences in ET-1 protein localization or levels at 42 days post infection in sham- and CVB3-infected animals. Finally, in situ hybridization and TUNEL staining were performed to assess viral localization and cell death in CVB3-infected hearts. There was no detectable CVB3 or TUNEL positivity in the endothelium of coronary arteries. Therefore, late impairment of endothelial-dependent vasorelaxation of coronary resistance vessels in CVB3-induced myocarditis does not appear to involve altered ET-1 expression but may be secondary to decreased stimulated NO secretion by the endothelium.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Bosentan; Coronary Vessels; Coxsackievirus Infections; Endothelin-1; Endothelium, Vascular; In Situ Nick-End Labeling; Male; Mice; Models, Cardiovascular; Myocarditis; Sulfonamides; Vasodilation; Vasodilator Agents

Renin angiotensin system contributes to activation of circulating endothelin in congestive heart failure. To investigate the effects of angiotensin II receptor antagonist and angiotensin converting enzyme inhibitors (ACEI) on the levels of endothelin-1 (ET-1), we administered orally angiotensin II type 1 receptor (AT1) antagonist, L-158,809 (ATA) (6, 1.2 and 0.12 mg/kg/day), enalapril (1 mg/kg/day) and captopril (7.5 mg/kg/day) for 14 days to mice with viral myocarditis, beginning 7 days after encephalomyocarditis virus (500 pfu/mouse) inoculation. Plasma ET-1, cardiac ET-1, heart weight (HW) and HW/ body weight (BW) ratio were examined and compared with infected untreated mice. Moreover, the HW (mg) and HW/BW (x 10(-3)) ratio were significantly (P<0.05) reduced in mice treated with ATA and ACEIs in comparison with infected control. ACEIs and higher dosed of ATA reduced myofiber hypertrophy. Both of plasma and cardiac ET-1 proteins were significantly elevated in infected control compared with uninfected normal mice. Plasma ET-1 was significantly (P<0.01) reduced in mice with three different concentrations of ATA but were not decreased in mice with captopril or enalapril compared with infected control. The expression of endothelin-1 mRNA was significantly reduced in mice with ATA in comparison with infected untreated mice by competitive RT-PCR. ATA reduced ET-1 protein and mRNA in the myocardium of mice with myocarditis, improving congestive heart failure and myofiber hypertrophy. We suggest the effect of ATA on the reduction of endothelin has a different pathway from angiotensin converting inhibitor and that ATA seems to be a useful agents for congestive heart failure due to viral myocarditis.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovirus Infections; Encephalomyocarditis virus; Endothelin-1; Female; Mice; Mice, Inbred C3H; Myocarditis; Organ Size; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Serine elastases degrade elastin, stimulate vascular smooth muscle cell migration and proliferation, and are associated with myocardial damage. To evaluate the impact of elastase inhibition on cardiovascular development and disease, transgenic mice were created in which the mouse preproendothelin-1 promoter was used to target elafin overexpression to the cardiovascular system. To distinguish the transgene from endogenous elafin, constructs were made incorporating a FLAG sequence; the COOH-terminus FLAG-tagged elafin construct produced a stable, functionally active gene product and was used to create transgenic mice. Consistent with endothelin expression, abundant elafin mRNA was observed in transgenic F1 embryos (embryonic day 13.5) and in adult transgenic mice heart, trachea, aorta, kidney, lung, and skin, but not in liver, spleen, and intestine. Functional activity of the transgene was confirmed by heightened myocardial elastase inhibitory activity. No tissue abnormalities were detected by light microscopy or elastin content. However, injection of 10 plaque-forming units (PFU) of encephalomyocarditis virus resulted in death within 11 days in 10 out of 12 nontransgenic mice compared with one out of nine transgenic littermates. This reduced mortality was associated with better cardiac function and less myocardial inflammatory damage. Thus, elafin expression may confer a protective advantage in myocarditis and other inflammatory diseases.

Topics: Animals; Cardiovirus Infections; Cattle; Cells, Cultured; Disease Models, Animal; Elastin; Encephalomyocarditis virus; Endothelin-1; Endothelins; Endothelium, Vascular; Gene Expression; Humans; Mice; Mice, Transgenic; Myocarditis; Myocardium; Pancreatic Elastase; Protein Precursors; Proteinase Inhibitory Proteins, Secretory; Proteins; Pulmonary Artery; Recombinant Fusion Proteins; Serine Proteinase Inhibitors; Sheep; Tissue Distribution

Endothelin (ET) is one of the most important contributing factors in the pathophysiology of cardiovascular diseases. However, little is known about its role in myocarditis.. Four-week-old DBA/2 mice were inoculated with the encephalomyocarditis virus. Expression levels of ET-converting enzyme-1 (ECE-1) and prepro-ET-1 mRNA were significantly increased at 7 and 14 days after virus inoculation. Plasma and myocardial ET-1 levels were significantly higher in infected than noninfected mice between 5 and 14 days after virus inoculation. Immunohistochemical analyses revealed that not only endothelial cells and myocytes but also infiltrating mononuclear cells produced ET-1 protein at 7 days. Oral bosentan, a mixed ET-1 receptor antagonist, was administered after virus inoculation in doses of 0 (control group), 10, or 100 mg. kg(-1). d(-1), and the animals were killed on day 14. Mean heart weight/body weight ratios were 8.3+/-1.8 versus 11.2+/-2.4 versus 10. 8+/-2.4 in the bosentan 100 mg. kg(-1). d(-1) versus 10 mg. kg(-1). d(-1) versus control groups, respectively (P<0.05). Corresponding histological scores for myocardial necrosis were 2.0+/-0.2 versus 2. 9+/-0.3 versus 3.0+/-0.4 (P<0.05), and cellular infiltration scores were 2.3+/-0.3 versus 2.9+/-0.4 versus 3.3+/-0.4 (P<0.05). Animals killed on day 5 had significantly smaller necrotic areas after treatment with bosentan 100 mg. kg(-1). d(-1) than the group treated with a lower dose or the control group, despite the absence of differences in virus titers.. This study suggests that ET-1 plays an important pathophysiological role in viral myocarditis. Treatment with bosentan had a cardioprotective effect without modifying viral replication.

Topics: Animals; Antihypertensive Agents; Aspartic Acid Endopeptidases; Bosentan; Cardiovirus Infections; Disease Models, Animal; Encephalomyocarditis virus; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Heart; Male; Metalloendopeptidases; Mice; Mice, Inbred DBA; Myocarditis; Myocardium; Protein Precursors; RNA, Messenger; Sulfonamides

Endothelin-1 (ET-1) is known to have positive inotropic effects in isolated cardiac muscle strips. ET-1 levels are elevated in congestive heart failure (CHF). We investigated the effects of ET-1 on contractility and cardiac relaxation (lusitropy) of the intact healthy murine heart and myocarditic/cardiomyopathic heart by chronic oral treatment with a mixed ETA/ETB blocker SB217242. Chronic ET-1 blockade of normal hearts resulted in depression of contractility and lusitropy of the normal heart but preservation and enhancement of contractility and lusitropy in myocarditic animals, in which ET-1 cardiac content is elevated. This suggests that ET-1 is important in the basal contractility and relaxation of the normal heart but that its chronic elevation in CHF causes impairment of cardiac systolic and diastolic performance.

Topics: Animals; Carboxylic Acids; Cardiomyopathy, Dilated; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Indans; Male; Mice; Mice, Inbred DBA; Myocardial Contraction; Myocarditis; Myocardium; Receptor, Endothelin A