Inhibition of apoptosis by progesterone in cardiomyocytes
Stephen Morrissy,
Beibei Xu,
David Aguilar,
Jack Zhang,
Qin M. Chen,
Stephen Morrissy
Present address: Cleveland Clinic Foundation R2, Cleveland, OH, USA.
Search for more papers by this authorBeibei Xu
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA
Search for more papers by this authorDavid Aguilar
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA
Search for more papers by this authorJack Zhang
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA
Search for more papers by this authorQin M. Chen
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA
Search for more papers by this authorStephen Morrissy,
Beibei Xu,
David Aguilar,
Jack Zhang,
Qin M. Chen,
Stephen Morrissy
Present address: Cleveland Clinic Foundation R2, Cleveland, OH, USA.
Search for more papers by this authorBeibei Xu
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA
Search for more papers by this authorDavid Aguilar
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA
Search for more papers by this authorJack Zhang
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA
Search for more papers by this authorQin M. Chen
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA
Search for more papers by this authorQin M. Chen, Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA. Tel.: (520)626-9126; fax (520)626-2204; e-mail: [email protected]
Summary
While gender-based differences in heart disease have raised the possibility that estrogen (ES) or progesterone (PG) may have cardioprotective effects, recent controversy regarding hormone replacement therapy has questioned the cardiac effects of these steroids. Using cardiomyocytes, we tested whether ES or PG has protective effects at the cellular level. We found that PG but not ES protects cardiomyocytes from apoptotic cell death induced by doxorubicin (Dox). PG inhibited apoptosis in a dose-dependent manner, by 12 ± 4.0% at 1 μm and 60 ± 1.0% at 10 μm. The anti-apoptotic effect of PG was also time dependent, causing 18 ± 5% or 62 + 2% decrease in caspase-3 activity within 1 h or 72 h of pretreatment. While PG causes nuclear translocation of its receptor within 20 min, the cytoprotective effect of PG was canceled by mifepristone (MF), a PG receptor antagonist. Analyses using Affymetrix high-density oligonucleotide array and RT-PCR found that PG induced Bcl-xL, metallothionine, NADPH quinone oxidoreductase 1, glutathione peroxidase-3, and four isoforms of glutathione S-transferase. Western blot analyses revealed that PG indeed induced an elevation of Bcl-xL protein in a dose- and time-dependent manner. Nuclear run-on assay indicated that PG induced Bcl-xL gene transcription. Inhibiting the expression of Bcl-xL using siRNA reduced the cytoprotective effect of PG. Our data suggests that PG induces a cytoprotective effect in cardiomyocytes in association with induction of Bcl-xL gene.
Supporting Information
Table S1 Genes upregulated by PG in cardiomyocytes.
Table S2 Genes downregulated by PG in cardiomyocytes.
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