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Transgenic Mice Overexpressing Growth Hormone (GH) Have Reduced or Increased Cardiac Apoptosis through Activation of Multiple GH-Dependent or -Independent Cell Death Pathways

Department of Endocrinology and Metabolism (F.B., D.R., F.R., F.U., E.M.), University of Pisa, 56124 Pisa, Italy; SantAnna School of Advanced Studies (C.U.), 56127 Pisa, Italy; Department of Endocrinology (M.G.), University of Molise, 86100 Campobasso, Italy; and Department of Clinical Medicine (L.B.), University of Insubria, 21100 Varese, Italy

Address all correspondence and requests for reprints to: Fausto Bogazzi, M.D., Ph.D., Department of Endocrinology and Metabolism, University of Pisa, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy. E-mail: f.bogazzi{at}endoc.med.unipi.it or fbogazzi{at}hotmail.com.

GH has antiapoptotic effects in cardiac or noncardiac cell lines; however, increased apoptosis has been found in myocardial samples of patients with acromegaly. The aim of this study was to investigate cardiac apoptosis and underlying molecular mechanisms in transgenic mice overexpressing bovine GH [acromegalic mice (Acro)] aged 3 or 9 months. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase assay and annexin V; expression of pro- or antiapoptotic proteins was assessed by Western blot. Specificity of GH action was confirmed using a selective GH receptor antagonist. Apoptosis was lower in 3-month-old Acro than in controls; reduction was abolished by a GH receptor antagonist. The effects of GH were consistent with an antiapoptotic phenotype (increased Bcl2 and Bcl-XL and reduced Bad and cytochrome c levels, leading to lower activation of caspase-9 and caspase-3). In contrast, apoptosis was higher in 9-month-old Acro than in littermate controls; in addition, a GH receptor antagonist was without effect; the proapoptotic phenotype consisted in increased Bad, cytochrome c, caspase-9, and caspase-3. GH reduced apoptosis through p38 and p44/42 kinase pathways at young ages, whereas phosphatidylinositol-3-kinase was silent; on the contrary, the effects of GH on p38 and p44/42 kinase pathways were overcome by GH-independent stimuli in 9-month-old Acro. In addition, the antiapoptotic effect of GH was still present at this age as shown by phosphatidylinositol-3-kinase/Akt pathway activation. In conclusion, chronic GH excess reduced apoptosis at a young age, whereas its antiapoptotic action was overwhelmed in older animals by GH-independent mechanisms, leading to increased cell death.

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