The conserved phosphoinositide 3-kinase pathway determines heart size in mice

Abstract

Phosphoinositide 3-kinase (PI3K) has been shown to regulate cell and organ size in Drosophila, but the role of PI3K in vertebrates in vivo is not well understood. To examine the role of PI3K in intact mammalian tissue, we have created and characterized transgenic mice expressing constitutively active or dominantnegative mutants of PI3K in the heart. Cardiacspeci®c expression of constitutively active PI3K resulted in mice with larger hearts, while dominantnegative PI3K resulted in mice with smaller hearts. The increase or decrease in heart size was associated with comparable increase or decrease in myocyte size. Cardiomyopathic changes, such as myocyte necrosis, apoptosis, interstitial ®brosis or contractile dysfunction, were not observed in either of the transgenic mice. Thus, the PI3K pathway is necessary and suf®-cient to promote organ growth in mammals.

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

“…Cardiomyocyte-specific transgenic (Tg) mice (FVB/N background) with increased PI3K (p110α) activity (constitutively active PI3K [p110α], caPI3K) or decreased PI3K(p110α) activity (dominant-negative PI3K [p110α], dnPI3K) were originally generated and provided by S. Izumo (Beth Israel Deaconess Medical Center, Boston, MA, USA) [20]. Compared with non-transgenic (Ntg) mice, caPI3K-Tg mice have elevated cardiac PI3K(p110α) activity, normal cardiac function and hearts that are 20% larger (physiological hypertrophy) [20], while dnPI3K-Tg mice have reduced cardiac PI3K(p110α) activity, normal cardiac function and hearts that are 20% smaller.…”

“…Northern blot analysis Northern blot analysis was performed as previously reported [20]. Total RNA (10 μg) was electrophoresed in 1.3% denaturing formaldehydeagarose gels and blotted onto Hybond-N membranes (GE Healthcare, Rydalmere.…”

Celecoxib modulates hypertrophic signalling and prevents load‐induced cardiac dysfunction

“…Analyzing the degree of Akt activation may help to resolve this potential paradox. Whereas in the studies demonstrating protective effects the level of Akt phosphorylation was rather moderate (1.5-to 6-fold) [12,[29][30][31], the level of Akt activity in studies with maladaptive effects was much higher (15-to 80-fold) [14,27,28]. Therefore, it appears that the character of hypertrophy is determined by the degree of Akt activity.…”

“…Accordingly, it appears consistent that a pharmacologically controlled inhibition of Akt activity by celecoxib has cardioprotective effects. However, there are also numerous studies documenting beneficial effects of Akt activation in the heart [12,[29][30][31]. Moreover, physiological hypertrophy in response to exercise training is accompanied by higher levels of activated Akt [12].…”

“…Moreover, physiological hypertrophy in response to exercise training is accompanied by higher levels of activated Akt [12]. Transgenic overexpression of PI3K [30], IGF-1 [31], or the IGF-1 receptor [29], resulting in higher Akt activity, are accompanied by preserved cardiac function. Furthermore, activation of Akt has a pivotal regulatory role for normal postnatal growth of the heart [11].…”