Table 2.
Predicted interaction of T3-induced miRNA expression and hypertrophic signaling pathways.
| mRNA | miR | Induction | Reference | |
|---|---|---|---|---|
| UPREGULATED TARGET MRNAS INVOLVED IN PATHOLOGICAL HYPERTROPHY | ||||
| Map2k3 | 590 | Dominant negative Map2k3 increases hypertrophy | TAC, AngII, Iso | (41) |
| Map2k6 | 29b | Dominant negative Map2k6 increases hypertrophy | TAC, AngII, Iso | (41) |
| Slc8a1 | 721 | uced levels of Slc8a1 caused hypertrophy | TAC | (42) |
| DOWNREGULATED TARGET MRNAS INVOLVED IN PATHOLOGICAL HYPERTROPHY | ||||
| Agtr2 | 539 | Chronic loss of Agtr2 attenuates left ventricular hypertrophy | AngII | (43) |
| Camk2d | 539, 7b | Inhibition prevents maladaptive remodeling | TAC, Iso | (44, 45) |
| Ctgf | 124, 212, 18a | Inhibition attenuates LV remodeling in pressure overload-induced heart failure | TAC, AngII | (46, 47) |
| Ep300 | 212 | Specific reduction of Ep300 content or activity diminishes stress-induced hypertrophy | TAC | (48, 49) |
| Grb2 | 124, 141 | Grb2+/− mice showed a reduced hypertrophic response in response to overload | TAC | (50) |
| Hif-1α | 18a | Deletion of Hif-1α prevents hypertrophy | TAC | (51) |
| Htr2a | 34c | Blockade of Htr2a has a beneficial effect on the development of hypertrophy | TAC | (52) |
| Ikbkb | 503 | Ikbkb negatively regulates the anti-hypertrophic action of Irf7/Nf-kappa B in pathological hypertrophy | TAC, Pe, AngII | (53, 54) |
| Ptk2/Fak | 379 | uced levels of Ptk2 were accompanied by prevention, as well as reversal, of load- induced LV hypertrophy | TAC | (55) |
| Rapgef3 | 539, 721 | KO reduces β-adrenergic stimulation-induced hypertrophy | TAC | (56) |
| Rheb | 141 | Rheb activates mTORC1 signaling-dependent hypertrophy | TAC, MI | (57) |
| Tln1 | 124, 503 | uction of Tln1 expression improves cardiac remodeling | TAC | (58) |
| UPREGULATED TARGET MRNA INVOLVED IN PHYSIOLOGICAL HYPERTROPHY | ||||
| Akt | 302 | Increased Akt is involved in physiological hypertrophy | MI, Ex | (16, 59, 60) |
| Prkcd | 181c | Prkcd activates non-pathological hypertrophy | MI | (61) |
| DOWNREGULATED TARGET MRNA INVOLVED IN PHYSIOLOGICAL HYPERTROPHY | ||||
| Ctnnb1 | 141 | Down regulation is required for adaptive remodeling | AngII | (62) |
| Pik3ca | 124 | Constitutively active Pik3ca/p110α increases the hypertrophic response in TAC;, is activated in physiological hypertrophy | TAC, Ex | (63, 64) |
| Pla2g4a | 543 | Hypertrophic growth is increased in Pla2g4a−/− in TAC; increasing Igf-1 | TAC | (65) |
IPA and additional literature were used to evaluate the role of 27 bona fide target mRNAs in the development of cardiac hypertrophy (see Figure 4). Twenty of the initial 27 target mRNAs were shown to be validated in mouse models for cardiac hypertrophy, as indicated in the table, together with the relevant literature and description of the principal findings. These models included transverse (ascending) aortic constriction (TAC), LV remodeling following myocardial infarction (MI), and Angiotensin II (AngII), isoproterenol (Iso), and phenylephrine (Pe) induced pathological hypertrophy, and exercise (Ex) induced physiological hypertrophy. The identified T3-regulated miRNAs are depicted in green (reduced expression) or red (increased expression). The direction of change of the predicted target mRNAs is similarly color coded. Fifteen target mRNAs are predicted to be regulated by the indicated miRNAs in such a way that pathological signaling is suppressed. For example, Map2k3 has been shown in a TAC model to suppress pathological remodeling. Consequently, its upregulation by decreased miR-590 expression is considered to limit pathological signaling. Likewise, Camk2d is required for TAC-induced pathological remodeling and its suppression by the upregulated miRNAs 539 and 7b is again considered to limit pathological signaling. The remaining five target mRNAs are regulated in such a way that physiological signaling is enhanced.