Author:
Takakuma Akira,Nishii Mototsugu,Valaperti Alan,Hiraga Haruto,Saji Ryo,Sakai Kazuya,Matsumura Reo,Miyata Yasuo,Oba Nozomu,Nunose Fumiya,Ogawa Fumihiro,Tamura Kouichi,Takeuchi Ichiro
Abstract
AbstractCardioprotective effect of prostaglandin-E2 receptor-4 (EP4) stimulation on the ischemic heart has been demonstrated. Its effect on the heart affected by myocarditis, however, remains uncertain. In this study, we investigated therapeutic effect of EP4 stimulant using a mouse model of autoimmune myocarditis (EAM) that progresses to dilated cardiomyopathy (DCM). EP4 was present in the hearts of EAM mice. Treatment with EP4 agonist (ONO-0260164: 20 mg/kg/day) improved an impaired left ventricular (LV) contractility and reduction of blood pressure on day 21, a peak myocardial inflammation. Alternatively, DCM phenotype, characterized by LV dilation, LV systolic dysfunction, and collagen deposition, was observed on day 56, along with activation of matrix metalloproteinase (MMP)-2 critical for myocardial extracellular matrix disruption, indicating an important molecular mechanism underlying adverse ventricular remodeling after myocarditis. Continued treatment with ONO-0260164 alleviated the DCM phenotype, but this effect was counteracted by its combination with a EP4 antagonist. Moreover, ONO-0260164 inhibited in vivo proteolytic activity of MMP-2 in association with up-regulation of tissue inhibitor of metalloproteinase (TIMP)-3. EP4 stimulant may be a promising and novel therapeutic agent that rescues cardiac malfunction during myocarditis and prevents adverse ventricular remodeling after myocarditis by promoting the TIMP-3/MMP-2 axis.
Funder
Grant-in-Aid for Scientific Research
YOKOHMA ACADEMIC FOUNDATION
Publisher
Springer Science and Business Media LLC
Reference44 articles.
1. McCarthy, R. E. et al. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N. Engl. J. Med. 342, 690–695 (2000).
2. Ammirati, E. et al. Survival and left ventricular function changes in fulminant versus nonfulminant acute myocarditis. Circulation 136, 529–545 (2017).
3. Jin, O. et al. Detection of enterovirus RNA in myocardial biopsies from patients with myocarditis and cardiomyopathy using gene amplification by polymerase chain reaction. Circulation 82, 8–16 (1990).
4. Hühl, U., Noutsias, M., Seeberg, B. & Schultheiss, H. P. Immunohistochemical evidence for a chronic intramyocardial inflammatory process in dilated cardiomyopathy. Heart 75, 295–300 (1996).
5. Lauer, B., Padberg, K., Schultheiss, H. P. & Strauer, B. E. Autoantibodies against cardiac myosin in patients with myocarditis and dilated cardiomyopathy. Z. Kardiol. 84, 301–310 (1995).
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