Table 1.
Evidence from mouse models suggesting roles of GSK-3s in the heart
| Model | Cardiac Phenotype |
|---|---|
| Cardiac-specific Tg-GSK-3β-S9A | Suppressed or reversed cardiac hypertrophy in response to TAC, calcineurin activation, or adrenergic stimulation [10, 15] |
| Cardiac-specific Tg-GSK-3β-DN | Induction of compensatory hypertrophy, inhibition of apoptosis and fibrosis, and increased cardiac contractility after PO [12] |
| Cardiac-specific Tg-GSK-3β | Impaired post-natal cardiomyocyte growth and led to contractile dysfunction [14] |
| Cardiac-specific Tg-GSK-3α | Inhibited cardiac growth and PO-induced cardiac hypertrophy yet increased fibrosis and apoptosis [17] |
| GSK-3β S9A KI | Attenuated hypertrophy and HF under PO [13] |
| GSK-3αS21A KI | Increased hypertrophy and HF under PO [13] |
| GSK-3β germline KO | Died in mid gestation from inability to recruit pro-survival NF-κB signaling in setting of increased TNFβ production in response to pathogens [24]; In absence of pathogens, died in late gestation or immediately after birth due to near obliteration of the ventricular cavities by proliferating cardiomyocytes, DORV and VSD also seen [21] |
| GSK-3α KO | Born without apparent cardiac abnormalities [21, 25]; Development of cardiac hypertrophy and contractile dysfunction after 2-months of age; PO-induced increased hypertrophy and HF; impaired beta-adrenergic responsiveness [23] |
| Inducible cardiac-specific GSK-3β KO | Normal PO-induced hypertrophy; less LV dilatation and better-preserved LV function post MI; increased cardiomyocyte proliferation following PO and MI [22] |
| GSK-3β-S9A/GSK-3α S21A double KI | Normal post MI hypertrophy [26]; attenuated pathological hypertrophy induced by chronic adrenergic stimulation [27] |
Abbreviations: TG, transgenic; S9A, serine-9 mutated to alanine; S21A, serine-21 mutated to alanine; DN, dominant negative; KI, knock-in; KO, knockout; HF, heart failure; PO, pressure overload; DORV, double outlet right ventricle; VSD, ventricular septal defect; MI, myocardial infarction; LV, left ventricle. Please see text for additional abbreviations.