Cardiac hypertrophy: stressing out the heart
J. Clin. Invest. Jil C. Tardiff, et al. 116:1467 doi:10.1172/JCI28884 [Go to this article.]

Figure 1
Potential mechanism for the role of early βAR dysfunction in the hypertrophy-independent pathological phenotype induced by iTAC. (A) Role of PI3Kγ in modulating βAR internalization. Chronic β-agonist binding to βARs leads to an induction in myocellular βARK1 levels. βARK1 binds to PI3Kγ and facilitates its translocation to the receptor complex, where the subsequent generation of D-3 phosphoinositides leads to the recruitment of multiple adapter proteins and receptor internalization. (B) Intermittent pressure overload (iTAC) promotes early βAR dysfunction. Normal mice exposed to both 1 week and 4 weeks of iTAC exhibited significant βAR downregulation and desensitization. In the case of the 1-week iTAC mice, this effect was seen despite normal steady-state catecholamine levels and highlights the pathogenic nature of the pressure-overload stimulus. While the pressure-overload sensor mechanism is not fully understood, the participation of the molecules involved in mechanical stress (e.g., integrins) is likely. These 2 stimuli result in the observed pathogenic response, including a significant induction of βARK1 levels causing an increase in PI3Kγ translocation to the agonist-bound receptor complex and subsequent increase in receptor internalization. (C) Overexpression of PI3Kγ_inact in the heart reverses the downregulation of βARs and the early pathogenic changes in iTAC mice. Unlike normal mice, iTACγ_inact mice subjected to 1 week of iTAC exhibited normal βAR density and βAR/G_s coupling in the context of elevated βARK1. Overexpression of PI3Kγ_inact leads to a competitive displacement of all PI3K isoforms from the βARK1/PI3K complex. This displacement blocks the effects of the early induction of βARK1 caused by iTAC and effectively preserves βAR levels and function.