Phenotypic Spectrum Caused by Transgenic Overexpression of Activated Akt in the Heart

Abstract

The serine-threonine kinase, Akt, inhibits cardiomyocyte apoptosis acutely both in vitro and in vivo. However, the effects of chronic Akt activation in the heart are unknown. To address this issue, we generated transgenic mice (TG؉) with cardiac-specific expression of a constitutively active mutant of Akt (myr-Akt) driven by the myosin heavy chain-␣ promoter. Three TG؉ founders (9 -19 weeks) died suddenly with massive cardiac dilatation. Two viable TG؉ lines (TG564 and TG20) derived from independent founders demonstrated cardiac-specific transgene expression as well as activation of Akt and p70S6 kinase. TG564 (n ‫؍‬ 19) showed cardiac hypertrophy with a heart/body weight ratio 2.3-fold greater than littermates (n ‫؍‬ 17, p < 0.005). TG20 (n ‫؍‬ 18) had less marked cardiac hypertrophy with a heart/body weight ratio 1.6-fold greater than littermates (n ‫؍‬ 17, p < 0.005). Isolated TG564 myocytes were also hypertrophic with surface areas 1.7-fold greater than littermates (p < 0.000001). Echocardiograms in both lines demonstrated concentric hypertrophy and preserved systolic function. After ischemia-reperfusion, TG؉ had a 50% reduction in infarct size versus TG؊ (17 ؎ 3% versus 34 ؎ 4%, p < 0.001). Thus, chronic Akt activation is sufficient to cause a spectrum of phenotypes from moderate cardiac hypertrophy with preserved systolic function and cardioprotection to massive cardiac dilatation and sudden death.

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

“…Nuclear-targeted PKB overexpression has previously been shown to have several beneficial effects including enhanced contractility and protection from ischaemic injury [28], while sustained PKB activation can lead to hypertrophic cardiomyopathy primarily via phosphorylation of substrates localized to the cytoplasm [11,29], indicating that PKB not only plays important roles in the nuclei of cardiomyocytes, but that these roles can differ depending on its localization. Furthermore, we show that inhibition of PKB with triciribine causes ISO to behave as an inverse agonist, leading to the inhibition of RNA synthesis, as opposed to its previously noted stimulatory effect.…”

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

“…Akt itself is an important regulator of myocyte growth and survival, 25 and constitutive overexpression of Akt in transgenic mice has been found to lead to increased contractility 26 and pathological cardiac hypertrophy. 27,28 Clustered with Akt and gp130 was fibroblast growth factor-1, an angiogenic growth factor that has earlier been shown in human cardiac hypertrophy 29 and that may reflect that blood vessel recruitment is an important feature of normal tissue growth. 30 An increase in connective tissue growth factor (CTGF) expression was seen in late LVH, similar to findings in other models of cardiac hypertrophy, 31 and its well-characterized profibrotic effect, including its ability to induce cardiac fibroblast proliferation and also extracellular matrix expansion.…”

Celecoxib modulates hypertrophic signalling and prevents load‐induced cardiac dysfunction

“…Several studies have demonstrated deleterious effects of chronically upregulated Akt signalling in the heart [13,14,27,28]. Accordingly, it appears consistent that a pharmacologically controlled inhibition of Akt activity by celecoxib has cardioprotective effects.…”

“…The molecular mechanisms determining the difference between physiological and pathological hypertrophy are still poorly understood. Whereas some authors hypothesize distinct signalling systems for the different types of hypertrophy [1,[10][11][12], there is now growing evidence that identical pathways can induce both, adaptive and maladaptive hypertrophy, depending on the intensity and duration of their activation [13,[13][14][15].…”