Post-ischemic cardioprotective potential of exogenous ubiquitin in myocardial remodeling late after ischemia/reperfusion injury.

ABSTRACT

AIMS: Pretreatment with ubiquitin (UB) associates with preservation of heart function 3 days post-ischemia/reperfusion (I/R) injury. This study investigated the cardioprotective potential of exogenous UB late after myocardial I/R injury. To enhance the clinical relevance, UB treatment was started at the time of reperfusion and continued for 28 days post-I/R. MAIN METHODS: Mice underwent ligation of the left anterior descending coronary artery for 45 min. At the time of reperfusion, mice were treated with UB or saline which was continued until 28 days post-I/R. Heart function was measured at 3, 7, 14 and 28 days post-I/R using echocardiography. Biochemical parameters of the heart and serum cytokines/chemokines levels were measured 28 days post-I/R. KEY FINDINGS: I/R decreased heart function and induced LV dilation at all time points post-I/R. However, I/R + UB exhibited improved heart function throughout the observation period, while LV dilation was lower in I/R + UB group at 3, 14 and 28 days post-I/R. I/R-mediated increase in myocardial fibrosis, hypertrophy and apoptosis were significantly lower in I/R + UB vs. I/R. Collagen-1α1 and MMP-2 expression was lower, while MMP-9 and TIMP-2 expression was higher in I/R + UB vs. I/R. MYH-7B (hypertrophy marker) expression was lower in I/R + UB vs. I/R. GSK3ß activation was lower (vs. Sham), while activation of ERK1/2 (vs. I/R) and AKT (vs. Sham) was higher in I/R + UB. Serum levels of IL-6, G-CSF and IL-2 were lower in I/R + UB vs. I/R. SIGNIFICANCE: Post-ischemic UB treatment improves heart function, and associates with decreased myocardial fibrosis, apoptosis, hypertrophy and serum cytokine/chemokine levels.