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. 2018 Mar 5:9:182.
doi: 10.3389/fphar.2018.00182. eCollection 2018.

Ivabradine Treatment Reduces Cardiomyocyte Apoptosis in a Murine Model of Chronic Viral Myocarditis

Ge Li-Sha  1 , Liu Li  2   3 , Zhou De-Pu  2 , Shi Zhe-Wei  2 , Gu Xiaohong  4 , Chen Guang-Yi  2 , Li Jia  2 , Lin Jia-Feng  2 , Chu Maoping  4 , Li Yue-Chun  2
Affiliations

Ivabradine Treatment Reduces Cardiomyocyte Apoptosis in a Murine Model of Chronic Viral Myocarditis

Ge Li-Sha et al. Front Pharmacol. .

Erratum in

Abstract

This study was designed to explore the effects of ivabradine on cardiomyocyte apoptosis in a murine model of chronic viral myocarditis (CVMC). Mice were inoculated intraperitoneally with Coxsackievirus B3 at days 1, 14, and 28, respectively. On day 42, the mice were gavaged with ivabradine for 30 days until the 72nd day. The heart of infected mice was dilated and a large number of interstitial fibroblasts infiltrated into the myocardium on day 42. Compared with the untreated CVMC mice, mice treated with ivabradine showed a significant reduction in heart rate and less impairment of left ventricular function on day 72. The positive apoptosis of myocardial cells in the untreated CVMC group was significantly higher than that of the normal group and was significantly reduced after treatment with ivabradine. The expression levels of Bax and Caspase-3 in the untreated CVMC group were significantly higher than those of the normal group and were apparently reduced in the ivabradine-treated group versus the untreated CVMC group. Bcl-2 showed a high expression in the normal group and low expression in the untreated CVMC group, but its expression level in the ivabradine-treated group were higher than that of the untreated CVMC group. These results indicate that ivabradine could attenuate the expression of Caspase-3 by downregulation of Bax and upregulation of Bcl-2 to prevent the deterioration of cardiac function resulting from ventricular myocyte loss by cardiomyocyte apoptosis.

Keywords: cardiomyocyte apoptosis; chronic viral myocarditis; coxsackievirus; heart rate; ivabradine.

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Figures

FIGURE 1
FIGURE 1
The heart rate in Normal control 2 group (n = 8), Normal + IVA group (n = 8), CVMC + IVA group (n = 8), and CVMC2 group (n = 8) on the 72nd day. Treatment with ivabradine (IVA) significantly reduced heart rate in CVMC+IVA group versus CVMC2 group. ∗P < 0.05 vs. Control (Normal control 2 group), #P < 0.05 vs. CVMC2.
FIGURE 2
FIGURE 2
The echocardiography results in Normal control 1 group (n = 8) and CVMC1 group (n = 8) on the 42nd day. The LVEDd and LVESd were significantly dilated and the LVEF and LVFS in CVMC1 group were significantly lower than those of normal control group on day 42. (A) LVEDd = left ventricular end diastolic dimension, (B) LVESd = left ventricular end systolic dimension, (C) LVEF = left ventricular ejection fraction, and (D) LVFS = left ventricular shortening fraction. ∗P < 0.05 vs. Normal (Normal control 1 group).
FIGURE 3
FIGURE 3
The echocardiography results in Normal control 2 group (n = 8), Normal + IVA group (n = 8), CVMC + IVA group (n = 8), and CVMC2 group (n = 8) on the 72nd day. Treatment with ivabradine (IVA) significantly reduced the left ventricular internal diameter and apparently increased the LVEF and LVFS in CVMC+IVA group as compared to that in CVMC2 group. LVEDd = left ventricular end diastolic dimension, LVESd = left ventricular end systolic dimension, LVEF = left ventricular ejection fraction, LVFS = left ventricular shortening fraction. ∗P < 0.05 vs. Control (Normal control 2 group), #P < 0.05 vs. CVMC2.
FIGURE 4
FIGURE 4
HE staining on the 42nd day. HE staining revealed that the heart was dilated and a large number of interstitial fibroblasts had infiltrated into the myocardium in CVMC1 group. A (× 40) and C (× 400) are for Normal control 1 group. B (× 40) and D (× 400) are for CVMC1 group.
FIGURE 5
FIGURE 5
HE staining on the 72nd day. The heart chambers were shrunken and less interstitial fibroblasts infiltrated after treatment with ivabradine (IVA) in CVMC+IVA group as compared to that in CVMC2 group. (A) Normal control 2 group, (B) Normal+IVA group, (C) CVMC+IVA group, and (D) CVMC2 group.
FIGURE 6
FIGURE 6
Detection of apoptotic cardiomyocytes with the TUNEL assay on the 72nd day. Apoptotic cells were labeled green and are indicated by the yellow arrows (left panel) and the corresponding cardiomyocyte were stained blue with DAPI (right panel). (A) Normal control 2 group, (B) Normal+IVA group, (C) CVMC+IVA group, and (D) CVMC2 group.
FIGURE 7
FIGURE 7
The positive apoptotic cells per cm2 of TUNEL assay in each groups (n = 8). The apoptotic percentages in CVMC+IVA group significantly attenuated after treatment with ivabradine (IVA) compared with CVMC2 group. ∗P < 0.05 vs. Control (Normal control 2 group), #P < 0.05 vs. CVMC2.
FIGURE 8
FIGURE 8
WB analysis for Bax, Bcl-2, and Caspase-3 in each groups (n = 8). Treatment with ivabradine (IVA) significantly reduced the expression levels of Bax and Caspase-3, and increased the expression level of Bcl-2. ∗P < 0.05 vs. Control (Normal control 2 group), #P < 0.05 vs. CVMC2.
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