Hypoxia‐inducible factor‐1 improves inotropic responses of cardiac myocytes in ageing heart without affecting mitochondrial activity

Abstract

Ageing reduces the ability of cardiac myocytes to respond to inotropic agents. We hypothesized that hypoxia-inducible factor-1 (HIF-1) would improve the functional and Ca(2+) transient responses of ageing myocytes to the inotropic agents and this would act, in part, through altered mitochondrial activity. Young (3-4 months) and older Fischer 344 rats (18-20 months) were used. Hypoxia-inducible factor-1alpha was upregulated with ciclopirox olamine (CPX, 50 mg kg(1) on 2 days). Hypoxia-inducible factor-1 upregulation was detected by Western blot. Cardiomyocyte contraction and Ca(2+) transients were measured at baseline and after forskolin and ouabain. We also measured mitochondrial complex activities and production of reactive oxygen species (ROS). In the young group, forskolin (31%) and ouabain (31%) significantly increased percentage shortening. Similar changes were observed in the young + CPX group. Calcium transients also responded in a similar manner. However, in the older group, forskolin (12%) and ouabain (6%) did not significantly increase myocyte contractility or Ca(2+) transients. In the older + CPX group, the effects of forskolin (34%) and ouabain (29%) were restored. In the young + CPX group, there was increased ROS production and mitochondrial complex I and III activity compared with the young group. These differences were not observed in older groups. These data demonstrate an impaired functional and Ca(2+) effect of positive inotropic agents in older myocytes. Upregulation of HIF-1 restored this blunted response, but this was not related to changed mitochondrial activity induced by HIF-1. Thus, we found that HIF-1 improved inotropy in older myocytes without requiring mitochondrial activity changes.