Byung-Kwan Lim1, Soo-Hyeon Yun2, Eun-Seon Ju2, Bo-Kyoung Kim3, You-Jung Lee2, Dong-Kyeom Yoo4, Young-Chul Kim3, Eun-Seok Jeon5. 1. Department of Biomedical Science, Jungwon University, Goesan-gun, South Korea. 2. Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 3. Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, South Korea. 4. Center for Molecular & Cellular Imaging, Samsung Biomedical Research Institute, Seoul, South Korea. 5. Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: esjeon1107@gmail.com.
Abstract
BACKGROUND: Coxsackievirus B3 (CVB3) is a common cause of myocarditis and dilated cardiomyopathy. CVB3 3C protease (3CP) cleaves the viral polyprotein during replication. We tested whether a water soluble 3CP inhibitor (3CPI) had antiviral effects in a chronic myocarditis model. METHODS: Chronic myocarditis was established using DBA/2 strain mice. Starting on post-infection (p.i) day 3, CVB3-infected mice (n=41) were treated with 3CPI by daily intraperitoneal (i.p.) injection at a concentration of 50 μM (1.7 mg/kg/day) per day for 3 consecutive days. Additional mice (n=49) were injected with PBS as a control. RESULTS: The 5-week survival rate was significantly higher with 3CPI treatment (82.3% versus 47.9%; P<0.05). Organ virus titers at day 3 and 7 and myocardial damage were significantly lower in 3CPI-treated mice. Echocardiography at day 31 indicated strong protection of heart function by 3CPI (FS, 51.2±1.5 versus 26.1±1.5%; P<0.001). Hemodynamic measurements indicated that 3CPI treatment markedly reduced CVB3-induced LV dysfunction on day 31 (dP/dTmax, 5302±352 versus 4103±408 mmHg/s, P<0.05; dP/dTmin, -3798±212 versus -2814±206 mmHg/s, P<0.01). CONCLUSIONS: Water soluble 3CPI was delivered through i.p. injection after CVB3 infection. This agent preserved heart function and decreased organ viral titers and myocardial damage. Soluble 3CPI may be beneficial in the treatment of cardiomyopathy associated with enterovirus infection.
BACKGROUND:Coxsackievirus B3 (CVB3) is a common cause of myocarditis and dilated cardiomyopathy. CVB3 3C protease (3CP) cleaves the viral polyprotein during replication. We tested whether a water soluble 3CP inhibitor (3CPI) had antiviral effects in a chronic myocarditis model. METHODS:Chronic myocarditis was established using DBA/2 strain mice. Starting on post-infection (p.i) day 3, CVB3-infectedmice (n=41) were treated with 3CPI by daily intraperitoneal (i.p.) injection at a concentration of 50 μM (1.7 mg/kg/day) per day for 3 consecutive days. Additional mice (n=49) were injected with PBS as a control. RESULTS: The 5-week survival rate was significantly higher with 3CPI treatment (82.3% versus 47.9%; P<0.05). Organ virus titers at day 3 and 7 and myocardial damage were significantly lower in 3CPI-treated mice. Echocardiography at day 31 indicated strong protection of heart function by 3CPI (FS, 51.2±1.5 versus 26.1±1.5%; P<0.001). Hemodynamic measurements indicated that 3CPI treatment markedly reduced CVB3-induced LV dysfunction on day 31 (dP/dTmax, 5302±352 versus 4103±408 mmHg/s, P<0.05; dP/dTmin, -3798±212 versus -2814±206 mmHg/s, P<0.01). CONCLUSIONS:Water soluble 3CPI was delivered through i.p. injection after CVB3 infection. This agent preserved heart function and decreased organ viral titers and myocardial damage. Soluble 3CPI may be beneficial in the treatment of cardiomyopathy associated with enterovirus infection.
Authors: Kathleen E Simpson; Gregory A Storch; Caroline K Lee; Kent E Ward; Saar Danon; Catherine M Simon; Jeffrey W Delaney; Alan Tong; Charles E Canter Journal: Pediatr Cardiol Date: 2015-10-26 Impact factor: 1.655