Carvedilol Inhibits Matrix Metalloproteinase-2 Activation in Experimental Autoimmune Myocarditis: Possibilities of Cardioprotective Application

2017 ◽  
Vol 23 (1) ◽  
pp. 89-97 ◽  
Author(s):  
Monika Skrzypiec-Spring ◽  
Katarzyna Haczkiewicz ◽  
Agnieszka Sapa ◽  
Tomasz Piasecki ◽  
Joanna Kwiatkowska ◽  
...  
Keyword(s):  
Heart Failure ◽  
Troponin I ◽  
Heart Function ◽  
Heart Diseases ◽  
Acute Myocarditis ◽  
Study Groups ◽  
Matrix Metalloproteinase 2 ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Aims: Acute myocarditis is a potentially lethal inflammatory heart disease that frequently precedes the development of dilated cardiomyopathy and subsequent heart failure. At present, there is no effective standardized therapy for acute myocarditis, besides the optimal care of heart failure and arrhythmias in accordance with evidence-based guidelines and specific etiology-driven therapy for infectious myocarditis. Carvedilol has been shown to be cardioprotective by reducing cardiac pro-inflammatory cytokines present in oxidative stress in certain heart diseases. However, effects of carvedilol administration in acute myocarditis with its impact on matrix metalloproteinases’ (MMPs) activation have not been elucidated. Methods and Results: Carvedilol in 3 doses (2, 10, and 30 mg/kg) was given daily to 3 study groups of rats (n = 8) with experimental autoimmune myocarditis by gastric gavage for 3 weeks. In comparison to untreated rats (n = 8) with induced myocarditis, carvedilol significantly prevented the left ventricle enlargement and/or systolic dysfunction depending on the dose in study groups. Performed zymography showed enhanced MMP-2 activity in untreated rats, while carvedilol administration reduced alterations. This was accompanied by prevention of troponin I release and myofilaments degradation in cardiac muscle tissue. Additionally, severe inflammatory cell infiltration was detected in the nontreated group. Carvedilol in all doses tested, had no impact on severity of inflammation. The severity of inflammation did not differ between study groups and in relation to the untreated group. Conclusions: The protective effects of carvedilol on heart function observed in the acute phase of experimental autoimmune myocarditis seem to be associated with its ability to decrease MMP-2 activity and subsequently prevent degradation of myofilaments and release of troponin I while not related to suppression of inflammation.

scholarly journals The Impact of Circulating Mitochondrial DNA on Cardiomyocyte Apoptosis and Myocardial Injury After TLR4 Activation in Experimental Autoimmune Myocarditis

2017 ◽  
Vol 42 (2) ◽  
pp. 713-728 ◽  
Author(s):  
Bangwei Wu ◽  
Huanchun Ni ◽  
Jian Li ◽  
Xinyu Zhuang ◽  
Jinjin Zhang ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Troponin I ◽  
Tissue Injury ◽  
H9c2 Cells ◽  
Autoimmune Myocarditis ◽  
Cardiac Inflammation ◽  
Experimental Autoimmune Myocarditis ◽  
Tlr4 Activation ◽  
The Impact ◽  
Experimental Autoimmune

Background/Aims: Mitochondrial DNA (mtDNA), acting as a newly found ‘danger-associated molecular patterns’ (DAMPs), is released into circulation upon tissue injury and performs as a considerable activator of inflammation and immune response. However, the role of circulating mtDNA in experimental autoimmune myocarditis (EAM) as well as Toll like receptor4 (TLR4) mediated cardiac inflammation and injury remains unknown. Methods: A model of EAM was established in BALB/c mice by immunization with porcine cardiac myosin. Lipopolysaccharide (LPS) was used to stimulate TLR4 activation in EAM mice and H9C2 cells. Results: LPS stimulation significantly aggravated cardiac inflammation and tissue injury in EAM, as demonstrated by increased myocardium inflammatory cell infiltration, and up-regulated inflammatory cytokines and troponin I(TnI) level in serum. Circulating mtDNA level was increased in EAM and TLR4 activation led to a greater elevation, which may be related to Reactive oxygen species (ROS) stress involved mtDNA damage characterized by reduced mtDNA copy number in myocardium tissue. In addition, the expression of Toll like receptor9 (TLR9), a ligand of mtDNA, was significantly up-regulated in the myocardium of EAM and EAM LPS group; meanwhile, TLR9 inhibition by ODN 2088 caused an inhibited apoptosis in LPS treated H9C2 cells. Moreover, in EAM and EAM LPS group, simultaneously giving ODN 2088 treatment significantly ameliorated cardiac inflammation and tissue injury compared with untreated group. Conclusion: Increased circulating mtDNA combined with upregulated TLR9 expression may corporately play a role in EAM as well as TLR4 activation mediated cardiac inflammation and injury.

scholarly journals Functional Proteomic Analysis of Experimental Autoimmune Myocarditis-Induced Chronic Heart Failure in the Rat

2010 ◽  
Vol 33 (3) ◽  
pp. 477-486 ◽  
Author(s):  
Yoshiki Sanzen ◽  
Minami Ito ◽  
Yoshimi Ohta ◽  
Yutaka Yoshida ◽  
Tomie Kawada ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Proteomic Analysis ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1–7 mas receptor

2012 ◽  
Vol 351 (2) ◽  
pp. 208-219 ◽  
Author(s):  
Vijayakumar Sukumaran ◽  
Punniyakoti T. Veeraveedu ◽  
Narasimman Gurusamy ◽  
Arun Prasath Lakshmanan ◽  
Ken’ichi Yamaguchi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Autoimmune Myocarditis ◽  
Mas Receptor ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Elevated aldolase 1A, retrogene 1 expression induces cardiac apoptosis in rat experimental autoimmune myocarditis model

2020 ◽  
Vol 98 (6) ◽  
pp. 373-382
Author(s):  
Seungmin Choi ◽  
Joo Hee Chung ◽  
Myung-Hee Nam ◽  
Eunjung Bang ◽  
Kwan Soo Hong ◽  
...  
Keyword(s):  
Cell Death ◽  
Drug Exposure ◽  
Caspase 3 ◽  
Acute Myocarditis ◽  
Cardiac Cells ◽  
Functional Protein ◽  
Autoimmune Myocarditis ◽  
Cardiac Apoptosis ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Acute myocarditis is an unpredictable heart disease that is caused by inflammation-associated cell death. Although viral infection and drug exposure are known to induce acute myocarditis, the molecular basis for its development remains undefined. Using proteomics and molecular analyses in myosin-induced rat experimental autoimmune myocarditis (EAM), we identified that elevated expression of aldolase 1A, retrogene 1 (Aldoart1) is critical to induce mitochondrial dysfunction and acute myocarditis development. Here, we demonstrate that cardiac cell death is associated with increased expressions of proapoptotic genes in addition to high levels of glucose, lactate, and triglyceride in metabolite profiling. The functional protein association network analysis also suggests that Aldoart1 upregulation correlates with high levels of dihydroxyacetone kinase and triglyceride. In H9c2 cardiac cells, lipopolysaccharides (LPS) or high glucose exposure significantly increases the cytochrome c release and the conversion of pro-caspase 3 into the cleaved form of caspase 3. We also found that LPS- or glucose-induced toxicities are almost completely reversed by siRNA-mediated knockdown of Aldoartl, which consequently increases cell viability. Together, our study strongly suggests that Aldoart1 may be involved in inducing mitochondrial apoptotic processes and can be a novel therapeutic target to prevent the onset of acute myocarditis or cardiac apoptosis.

scholarly journals Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy

2017 ◽  
Vol 214 (4) ◽  
pp. 943-957 ◽  
Author(s):  
Nicola L. Diny ◽  
G. Christian Baldeviano ◽  
Monica V. Talor ◽  
Jobert G. Barin ◽  
SuFey Ong ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Heart Function ◽  
Cell Type ◽  
Autoimmune Myocarditis ◽  
Large Numbers ◽  
Eosinophilic Myocarditis ◽  
Children And Young Adults ◽  
Experimental Autoimmune

Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in children and young adults. DCMi develops in up to 30% of myocarditis patients, but the mechanisms involved in disease progression are poorly understood. Patients with eosinophilia frequently develop cardiomyopathies. In this study, we used the experimental autoimmune myocarditis (EAM) model to determine the role of eosinophils in myocarditis and DCMi. Eosinophils were dispensable for myocarditis induction but were required for progression to DCMi. Eosinophil-deficient ΔdblGATA1 mice, in contrast to WT mice, showed no signs of heart failure by echocardiography. Induction of EAM in hypereosinophilic IL-5Tg mice resulted in eosinophilic myocarditis with severe ventricular and atrial inflammation, which progressed to severe DCMi. This was not a direct effect of IL-5, as IL-5TgΔdblGATA1 mice were protected from DCMi, whereas IL-5−/− mice exhibited DCMi comparable with WT mice. Eosinophils drove progression to DCMi through their production of IL-4. Our experiments showed eosinophils were the major IL-4–expressing cell type in the heart during EAM, IL-4−/− mice were protected from DCMi like ΔdblGATA1 mice, and eosinophil-specific IL-4 deletion resulted in improved heart function. In conclusion, eosinophils drive progression of myocarditis to DCMi, cause severe DCMi when present in large numbers, and mediate this process through IL-4.

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