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 hypertrophy. The goal of the current investigation was to determine if there was another explanation for the reduced LV/BW observed after inhibiting calcineurin with cyclosporine during the development of pressure overload LV hypertrophy as compared with animals that did not receive cyclosporine. Accordingly, 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 banding with and without chronic cyclosporine. Although LV/BW, compared to aortic banded vehicle treated mice, was reduced by 30% in aortic banded cyclosporine treated mice, myocyte cross sectional area was similar in both banded groups (346 +/- 9 mum(2) v 336 +/- 13 mum(2)). The volume percent interstitial 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 including myocytes containing iron were observed and were most prominent in aortic banded cyclosporine treated animals. Apoptosis, quantitated with TUNEL staining as percent of myocytes, was increased in aortic banded cyclosporine treated animals at 7 days (1.6 +/- 0.4%) compared with aortic banded vehicle treated animals (0.4 +/- 0.1%, P < 0.01) and was still increased at 21 days. Immunoblotting demonstrated a decrease in the phosphorylation of Akt and Bad, and also Bcl-2 levels were reduced in aortic banded cyclosporine treated animals at 7 days compared with aortic banded vehicle treated animals. These proteins protect against apoptosis, and support the concept that cyclosporine inhibited the calcineurin pathway, resulting in enhanced apoptosis, Thus. the decrease in LV/BW in the aortic banded cyclosporine treated animals actually may be due, at least in part, to cell loss and death, as reflected by the enhanced fibrosis and apoptosis and the focal iron deposits in myocyte., (C) 2001 Academic Press.