Abstract 18497: Caspase Inhibition Protects Cardiac Function with Chronic Pressure Overload by Reducing Non-Myocyte Apoptosis and Fibrosis not by Reducing Myocyte Apoptosis
It is widely held that a major mechanism underlying the transition from stable left ventricular (LV) function to failure is myocyte apoptosis with resultant loss of contractile elements. To test this hypothesis, we examined the effects of 3 weeks transverse aortic constriction (TAC) in C57BL/6 mice with or without administration of the caspase inhibitor (Z-Asp-2,6-DCBMk). In mice treated with the caspase inhibitor, LV function (LV ejection fraction) was preserved (66±3%)(n=8) compared with the vehicle group (54±3%)(n=9)(p<0.05) after 3 weeks of TAC. Caspase inhibition also prevented LV dilation after TAC. If the loss of function was due to significantly fewer myocytes in the vehicle group, then it is logical that LV mass would have been lower. Surprisingly, LVwt/tibial length was greater in the vehicle group (7.2±0.4) than with caspase inhibition (6.6±0.2), and apoptosis in the heart, determined by TUNEL assay, was 10fold greater, p<0.05, in non-myocytes after TAC than in myocytes (19.8±2.0 vs 1.4±0.2/10,000nuclei). Caspase inhibition reduced apoptosis by a similar percentage in non-myocytes and myocytes(34%), but since the numbers of apoptotic non-myocytes were 10fold greater, the absolute decrease in apoptosis was greater, p<0.05, in non-myocytes than myocytes (13.3±1.1 vs 0.9±0.1/10,000nuclei). Macrophages, important for fibrosis, were a major cell type protected from apoptosis by caspase inhibition. The amount of interstitial fibrosis increased less, p<0.05, after TAC with the caspase inhibitor (2.9±0.3 vs 5.1±0.8%) and was positively correlated with apoptosis in non-myocytes (R2=0.72), rather than in myocytes (R2=0.10). Immunostaining of connective tissue growth factor, a key fibrogenic protein, was also reduced with caspase inhibition. Thus, as expected, caspase inhibition reduced apoptosis, resulting in improved LV function following chronic pressure overload. However, since cells rescued by the caspase inhibitor were predominantly non-myocytes, it is unlikely that the rescue of LV function was due to preservation of contractile elements. It is more likely that the salutary action of caspase inhibition was due to a reduction in fibrosis, mediated by preservation of non-myocytes, e.g. macrophages.
- © 2010 by American Heart Association, Inc.