Doxorubicin induces early left ventricular dysfunction and metalloproteinase activation in rats

Abstract

Pathophysiological mechanism of the acute doxorubicin‐induced cardiotoxicity is not fully understood. The purpose of this study was to evaluate alterations in cardiac structure and function 48 hours after doxorubicin infusion in rats. Thus, male Wistar rats (n = 35) received an intraperitonealy single‐dose of doxorubicin (20 mg / kg) or saline (control group). Morphological, functional and biochemical analysis were performed. Echocardiographic analysis showed increased in isovolumetric relaxation time (20.3 ± 4.3 ms vs 24.7 ± 4.2 ms; p=0.007) and decreased left ventricular fractional shortening (0.59 ± 0.07 vs. 0.51± 0.05; p<0.001) in treated rats. This group also presented increased myocardial passive stiffness in isolated perfused heart study (14.7 ± 1.5 % vs 12 ± 2.2 %; p<0,05). There were no changes in TNF‐á, IFN‐ɤ, IL‐1 and ICAM‐1 or gene expression of ryanodine receptor, fosfolamban and Serca‐2a between groups. However, there were activation of MMP 2 (0.11 ± 0.01 vs 0.06 ± 0.02; p=0.002) and MMP 9 (0.07 ± 0.01 vs 0.05 ± 0.01; p=0.009) in the myocardium of the treated rats. In conclusion, doxorubicin caused early systolic and diastolic dysfunction, and this dysfunction is associated with increased MMP 2 and 9 activity.