Physiological myocardial hypertrophy is the result of adaptation of the heart to increased work demands on the cardiovascular system. This response is mediated by pathways which trigger increased protein synthesis and the consequent growth in cardiomyocyte (CMC) size. Multiple signaling pathways contribute to the physiological hypertrophy phenotype, of which one well studied is the IGF1-PI3K-Akt pathway. 1 This pathway is also involved in the mechanism of action of pro-angiogenic factors like vascular endothelial growth factor (VEGF), and leads to capillary formation and migration. 1, 2 We previously demonstrated that cardiac-specific overexpression of a constitutively active mutant of Akt (E40K-Akt) induces not only a physiological type of hypertrophy but also improvements in cardiac function by increasing L-type Ca2+ current and sarcoplasmic reticulum pump (SERCA) activity. 3 Accordingly, others found that with knockout of Akt-14 or overexpression of a dominant-negative PI3Ka mutant, 5 the physiological myocardial adaptations and hemodynamic improvements consequent to physical stress were prevented. Induction of pressure overload through transverse aortic constriction (TAC) is an established technique that permits the study of the effects of gene overexpression or knockout in mice undergoing heart failure. Models of overexpression of Akt in CMCs present with significant phenotypic variability (reviewed by Catalucci et al. 3). Constitutive or long-term overexpression of a myristilated (myr) form of Akt in CMCs were associated with negative effects on inotropism, either inducing heart failure or worsening cardiac function. 2 The negative effects of myr-Akt on cardiac function were reverted by expression of a constitutively active form of PI3Ka. 6 In contrast, cardiac-specific overexpression of myr-Akt improved cardiac function in the short-term: 2 here, Akt overexpression was accompanied by increased angiogenesis and VEGF protein expression. 2 Another interesting model of Akt overexpression is represented by cardiac-specific overexpression of a nuclear form of Akt, characterized by increased resistance to apoptosis and improved cardiac function. 7 We therefore assessed the effects of cardiac-specific overexpression of the E40K-Akt mutant on cardiac function in the TAC model of heart failure. We found that Akt ameliorates cardiac function by decreasing apoptosis and fibrosis and improving angiogenesis.

Transgenic mouse had significantly better cardiac function than WT after TAC during the course of our study (Figure 1a and Supplementary Tables 1–2, Supplementary Information). Phosphorylation of Akt at S473 in WT decreased significantly (three-/four-fold) only after 8 weeks of TAC. Levels in Tg mice were always greater (five-fold) than WT and never changed significantly (Figure 1b). Fetal gene expression was induced in both WT and in Tg mice after 1 week of TAC, but remained elevated at 8 weeks only in Tg mice (Figure 1c). We quantified capillaries in histological sections of hearts stained with FITC-conjugated lectin8 (Figure 1d, top). Under basal conditions, vascularization of Tg mouse myocardium was 1.8070. 15 capillaries/CMC as compared to 1.1570. 18 capillaries/CMC in WT controls (Figure 1d, bottom). One week after TAC, capillary density increased significantly in the myocardium of WT mice (1.5270. 06 capillaries/CMC), thus accompanying the adaptive hypertrophic response. Longterm exposure (8 weeks) to pressure overload did not induce any further increase of capillaries/CMC. In Tg mice, however, the baseline capillary/CMC ratio was greater than that found in WT mice, and did not change significantly, neither during …