Endothelin receptor antagonist exacerbates autoimmune myocarditis in mice.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: ktajiri@md.tsukuba.ac.jp.
Kazuko
K
Tajiri
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Satoshi
S
Sakai
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Taizo
T
Kimura
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Tomoko
T
Machino-Ohtsuka
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Nobuyuki
N
Murakoshi
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Dongzhu
D
Xu
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Zheng
Z
Wang
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Akira
A
Sato
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Takashi
T
Miyauchi
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Kazutaka
K
Aonuma
D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D018925:Chemokines / Q000096:biosynthesis; D018450:Disease Progression; D065128:Endothelin Receptor Antagonists / Q000009:adverse effects*; D019332:Endothelin-1 / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
D018925:Chemokines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D009218:Myosins
Autoimmune myocarditis; Endothelin; Inflammation; Suppressor of cytokine signaling