Abstract
Aim. Fibrosis had important effects on pressure overload-induced left ventricular (LV) dysfunction. High-mobility group box 1 (HMGB1), which was closely associated with fibrosis, was involved in the pressure overload-induced cardiac injury. This study determines the role of HMGB1 in LV dysfunction under pressure overload. Methods. Transverse aortic constriction (TAC) operation was performed on male C57BL/6J mice to build the model of pressure overload, while HMGB1 or PBS was injected into the LV wall. Cardiac function, collagen volume, and relevant genes were detected. Results. Echocardiography demonstrated that the levels of LV ejection fraction (LVEF) were markedly decreased on day 28 after TAC, which was consistent with raised collagen in the myocardium. Moreover, we found that the exposure of mice to TAC + HMGB1 is associated with higher mortality, BNP, and collagen volume in the myocardium and lower LVEF. In addition, real-time PCR showed that the expression of collagen type I, TGF-β, and MMP2 markedly increased in the myocardium after TAC, while HMGB1 overexpression further raised the TGF-β expression but not collagen type I and MMP2 expressions. Conclusion. This study indicated that exogenous HMGB1 overexpression in the myocardium aggravated the pressure overload-induced LV dysfunction by promoting cardiac fibrosis, which may be mediated by increasing the TGF-β expression.
Highlights
Heart failure has emerged as a major health problem during the past decades, but the underlying pathological mechanisms have not been fully disclosed
Echocardiographic assessment demonstrated that the levels of Aortic blood pressure (ABP), LV pressure (LVP), systolic blood pressure (SBP), and LV end-systolic pressure (LVESP) were significantly increased after Transverse aortic constriction (TAC) (P < 0.01) (Figure 1), while the levels of LV ejection fraction (LVEF) and LV fractional shortening (LVFS) were decreased, especially on day 28 after TAC (P < 0.01) (Figures 2(a) and 2(b)). ese results showed that pressure overload-induced left ventricular (LV) dysfunction models in mice were successfully built by TAC
Masson staining showed that no significant collagen was detected on days 0, 1, 3, 7, and 14 after TAC; increased collagen size was observed at 4 weeks after TAC (P < 0.01) (Figure 2(c)), which was consistent with decreased LV function. ese findings indicated that myocardial fibrosis was the key to pressure overload-induced LV dysfunction
Summary
Heart failure has emerged as a major health problem during the past decades, but the underlying pathological mechanisms have not been fully disclosed. Emerging studies have shown that HMGB1 may be an important mediator in fibrosis in the liver and renal diseases [8, 9] and in cardiovascular diseases [10,11,12] including experimental autoimmune myocarditis, postinfarction chronic heart failure, and diabetic cardiomyopathy. Combining these with our previous findings [13] that HMGB1 contributed to pressure overloadinduced cardiac hypertrophy and heart failure, the hypothesis seems reasonable in that HMGB1 may aggravate pressure overload-induced left ventricular dysfunction by mediating myocardial fibrosis.
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