Hypoxia-inducible factor-1 improves inotropic responses of cardiac myocytes in ageing heart without affecting mitochondrial activity.
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.
Department of Physiology and Biophysics, UMDNJ, Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ 08854, USA.
Tao
T
Tan
José
J
Marín-García
Shirish
S
Damle
Harvey R
HR
Weiss
D000375:Aging / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000077768:Ciclopirox; D005576:Colforsin / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011728:Pyridones; D017382:Reactive Oxygen Species; D000077768:Ciclopirox; D005576:Colforsin; D010042:Ouabain; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D002118:Calcium