Cyclosporine reduces left ventricular mass with chronic aortic banding in mice, which could be due to apoptosis and fibrosis

A tacit assumption in studies of left ventricular (LV) hypertrophy is that left ventricular/body weight (LV/BW) reflects the extent of myocyte hypertr ophy. The goal of the current investigation was to determine if there was a nother explanation for the reduced LV/BW observed after inhibiting calcineu rin with cyclosporine during the development of pressure overload LV hypert rophy as compared with animals that did not receive cyclosporine. According ly, we examined the prevalence of fibrosis and apoptosis and measured cell size in the hearts from mice at 1 and 3 weeks after transverse aortic bandi ng with and without chronic cyclosporine. Although LV/BW, compared to aorti c banded vehicle treated mice, was reduced by 30% in aortic banded cyclospo rine treated mice, myocyte cross sectional area was similar in both banded groups (346 +/- 9 mum(2) v 336 +/- 13 mum(2)). The volume percent interstit ial fibrosis was greater in aortic banded cyclosporine treated animals (1.4 +/- 0.2%) compared with aortic banded vehicle treated animals (0.9 +/- 0.2 %, P < 0.05) or in sham animals (0.6 +/- 0.1%), Surprisingly lesions includ ing myocytes containing iron were observed and were most prominent in aorti c banded cyclosporine treated animals. Apoptosis, quantitated with TUNEL st aining as percent of myocytes, was increased in aortic banded cyclosporine treated animals at 7 days (1.6 +/- 0.4%) compared with aortic banded vehicl e treated animals (0.4 +/- 0.1%, P < 0.01) and was still increased at 21 da ys. Immunoblotting demonstrated a decrease in the phosphorylation of Akt an d Bad, and also Bcl-2 levels were reduced in aortic banded cyclosporine tre ated animals at 7 days compared with aortic banded vehicle treated animals. These proteins protect against apoptosis, and support the concept that cyc losporine inhibited the calcineurin pathway, resulting in enhanced apoptosi s, Thus. the decrease in LV/BW in the aortic banded cyclosporine treated an imals actually may be due, at least in part, to cell loss and death, as ref lected by the enhanced fibrosis and apoptosis and the focal iron deposits i n myocyte., (C) 2001 Academic Press.