Apoptosis of cardiac myocytes in Gs alpha transgenic mice

The stimulatory GTP-binding protein Gs alpha transmits signals from catecho lamine receptors to activate adenylyl cyclase and thereby initiate a cascad e leading to cardiac chronotropy and inotropy. Transgenic mice overexpressi ng the Gs alpha subunit (Gs alpha) selectively in their hearts exhibit incr eased cardiac contractility in response to beta-adrenergic receptor stimula tion. However, with aging, these mice develop a cardiomyopathy. This study sought morphological and biochemical evidence that overexpression of Gs alp ha is associated with increased myocyte apoptosis in the older animals and to determine whether such overexpression can promote apoptosis of isolated neonatal cardiac myocytes exposed to beta-adrenergic receptor agonists, In the hearts of 15- to 18-month-old Gs alpha transgenic mice, histochemistry and electron microscopy illustrated the existence of numerous myocytes with abnormal nuclei embedded in collagen-rich connective tissue. Terminal deox yribonucleotide transferase-mediated dUTP nick-end labeling (TUNEL, for in situ labeling of DNA breaks) demonstrated that approximate to 0.6% of myocy te nuclei contained fragmented DNA. Agarose gel electrophoresis provided fu rther biochemical evidence of apoptosis by showing internucleosomal DNA fra gmentation. Cultured cardiac myocytes from newborn Gs alpha transgenic mice showed increased TUNEL staining and internucleosomal DNA fragmentation com pared with wild-type controls when treated with the beta-agonist isoprotere nol. Thus, enhanced activation of beta-adrenergic signaling by overexpressi on of Gs alpha in the hearts of transgenic mice induces apoptosis of cardia c myocytes. This represents a potential mechanism that may contribute to th e development of cardiomyopathy in this model.