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. 2016 Apr 7;20(8):1589–1602. doi: 10.1111/jcmm.12845

Figure 2.

Figure 2

Proposed IGF‐interaction with PPAR‐γ signalling in CVD epigenetics. Interaction between PPAR‐γ and MAPK/PI3K pathways happens at different levels or time points in the cell cycle, thus in certain situations PPAR‐γ reduces the expression of MEK1/2 protein expression and inhibits ERK1/2 phosphorylation 60, 146, 148. In contrast, in other cell systems, PPAR‐γ may activate ERK1/2. Furthermore, the interaction between PPAR‐γ and MAPK/PI3K may include pathways where ERK mediates PPAR‐γ phosphorylation, MEK1/2‐dependent PPAR‐γ nuclear export followed by PPAR‐γ degradation, PI3K inhibition through PTEN, mTOR decrease by AMPK activation and finally p70S6K phosphorylation. This signalling loop can be potentially responsible for epigenetic activity that targets survival, proliferation and/or differentiation of cardiac cells. Physical effort has been shown to increase levels of IGF‐I in muscle and physiological cardiac hypertrophy, thus inducing the IGF‐I/PI3K/Akt/P70S6K signalling pathway, and thereby increasing the protein synthesis required to build muscle; all of this can be epigenetically regulated 34, 60, 153, 154. On the other hand, PPAR‐γ ligands (such as rosiglitazone) activate tuberous sclerosis complex‐2 (TSC2) inhibiting mTOR signalling 152, 155 as a possible compensatory effect to the MEK/ERK action on PPAR‐γ.