Adaptive cardiac growth occurs as a feature of normal postnatal cardiac eutrophy or as the physiological hypertrophy resulting from exercise conditioning (12
). Maladaptive hypertrophy develops in response to excess hemodynamic workload; if the inciting pathologic stimulus is not removed, reactive hypertrophy that is initially a functional, although not essential, compensation (13
) inevitably undergoes ventricular remodeling/dilation, with functional decompensation and development of overt heart failure (16
). A third form of hypertrophy, also maladaptive, is caused by genetic mutations affecting sarcomeric or cytoskeletal proteins or proteins involved in calcium homeostasis and is reviewed elsewhere (17
). Thus, it is critical to define and distinguish among the pathways that regulate adaptive versus maladaptive hypertrophy in order to target the latter in human disease using novel pharmacological or gene transfer approaches.
Cardiac eutrophy and physiological hypertrophy are largely mediated by signaling through the peptide growth factors: IGF-1 and growth hormone (GH), the latter acting predominantly via increased production of IGF-1 (18
). When IGF-1, insulin, and other growth factors bind to their membrane tyrosine kinase receptors (Figure ), a 110-kDa lipid kinase, PI3K subgroup Iα (hereafter referred to as p110α) is activated (19
) and phosphorylates the membrane phospholipid phosphatidylinositol 4,5 bisphosphate at the 3′ position of the inositol ring. This leads to recruitment of the protein kinase Akt (also known as PKB) and its activator, 3-phosphoinositide–dependent protein kinase–1 (PDK1), to the cell membrane via interactions between kinase pleckstrin homology domains and the 3′-phosphorylated lipid (Figure ) (20
). This enforced colocalization of Akt and PDK1 causes the latter to phosphorylate and activate the former.
Figure 1 Mechanisms of activation of PI3K/Akt signaling in adaptive versus maladaptive hypertrophy. In adaptive hypertrophy, binding of growth factors to their cognate receptors triggers translocation of the PI3K isoform p110α to the cell membrane, a process (more ...)
Accumulated data suggest that PI3K/Akt signaling transduces adaptive cardiac hypertrophy. The whole-genome knockout of p110α was lethal at E9.5–E10.5 (showing a severe proliferative defect; ref. 21
) and therefore was of limited usefulness for cardiac studies. However, a central role of the p110α pathway in IGF-1–induced growth and normal and exercise-induced hypertrophy was demonstrated utilizing mice expressing constitutively active or dominant-negative mutants of PI3K specifically in the heart (22
). Strikingly, the adaptive hypertrophy seen with constitutive activation of cardiomyocyte PI3K did not transition into a maladaptive hypertrophy. In contrast, cardiac expression of a mutant dominant-negative p110α impaired normal eutrophic heart growth and prevented exercise-induced hypertrophy induced by swim training (23
). It is important to note that p110α was not, however, necessary for the hypertrophic response to pressure overload (although it may be important in the maintenance of left-ventricular function in the setting of pressure overload; ref. 23
). Further supporting a critical role for the PI3K/PDK1/Akt pathway in regulating normal heart growth is the finding that cardiac-specific ablation of PDK1 leads to reduced cardiac growth and a cardiomyopathic picture (24
). Finally, cardiac-specific inactivation of phosphatase and tensin homolog on chromosome 10 (PTEN), a tumor-suppressor phosphatase that negatively regulates the PI3K/Akt pathway by dephosphorylating 3′-phosphorylated phosphoinositides, resulted in cardiac hypertrophy (25
As noted above, a major kinase effector of PI3K signaling is Akt. Of the 3 Akt genes, only Akt1 and Akt2 are highly expressed in the heart. Cardiac-specific overexpression of constitutively active Akt mutants stimulates
heart growth that may (27
) or may not (28
) culminate in LV decompensation, likely depending on the degree of overexpression. In addition, expression of Akt confers protection from ischemia-induced cell death and cardiac dysfunction (27
). Consistent with the general trophic function of Akt, the Akt1 whole-genome–knockout mice weigh approximately 20% less than wild-type littermates and have a proportional reduction in size of all somatic tissues, including the heart (31
). In contrast, Akt2-knockout mice have only a modest reduction in organ size. Thus, data from the available Akt-knockout models support a critical role specifically for Akt1 in normal growth of the heart. Akt1/Akt2 double-knockout mice suffer from marked growth deficiency and a striking defect in cell proliferation. Investigating Akt1+/–
mice for resistance to hypertrophy and confirming these findings in a conditional, cardiac-specific Akt1-knockout model (thereby increasing the likelihood that the observed phenotype is secondary to the deletion of Akt1
rather than to the compensations for long-term, whole-body deletion of this essential kinase) will reevaluate long-standing concepts regarding a central role of Akt signaling in pathologic stress–induced hypertrophy and in the hypertrophic response to neurohormonal agonists (Figure ).
Akt is at a signaling cascade branch point. While its effects on cell death/survival are directly mediated via phosphorylation of the FOXO family of transcription factors and other regulators of apoptosis (20
), it is the 2 signaling branches downstream from Akt, not Akt itself, that largely determine the nature of a given hypertrophic response. One branch leads to mammalian target of rapamycin (mTOR) and the protein synthetic machinery, which is essential for all forms of hypertrophy (Figure and see below). The other branch leads to glycogen synthase kinase–3 (GSK-3), which also regulates the general protein translational machinery (Figure ) (32
) as well as specific transcription factor targets implicated in both normal and pathologic cardiac growth. Of note, activity of both of these branches can also be regulated by stress-activated, Gq-dependent mechanisms that are independent of Akt (Figure ) (32
), which likely explains in part the ability of the Akt1–/–
mouse heart to hypertrophy in response to pathologic stress.