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The lipid peroxidation product 4-hydroxy-trans-2-nonenal causes protein synthesis
in cardiac myocytes via activated mTORC1-p70S6K-RPS6 signaling
#MMPMID25617592
Calamaras TD
; Lee C
; Lan F
; Ido Y
; Siwik DA
; Colucci WS
Free Radic Biol Med
2015[May]; 82
(?): 137-46
PMID25617592
show ga
Reactive oxygen species (ROS) are elevated in the heart in response to
hemodynamic and metabolic stress and promote hypertrophic signaling. ROS also
mediate the formation of lipid peroxidation-derived aldehydes that may promote
myocardial hypertrophy. One lipid peroxidation by-product,
4-hydroxy-trans-2-nonenal (HNE), is a reactive aldehyde that covalently modifies
proteins thereby altering their function. HNE adducts directly inhibit the
activity of LKB1, a serine/threonine kinase involved in regulating cellular
growth in part through its interaction with the AMP-activated protein kinase
(AMPK), but whether this drives myocardial growth is unclear. We tested the
hypothesis that HNE promotes myocardial protein synthesis and if this effect is
associated with impaired LKB1-AMPK signaling. In adult rat ventricular
cardiomyocytes, exposure to HNE (10 ?M for 1h) caused HNE-LKB1 adduct formation
and inhibited LKB1 activity. HNE inhibited the downstream kinase AMPK, increased
hypertrophic mTOR-p70S6K-RPS6 signaling, and stimulated protein synthesis by 27.1
± 3.5%. HNE also stimulated Erk1/2 signaling, which contributed to RPS6
activation but was not required for HNE-stimulated protein synthesis.
HNE-stimulated RPS6 phosphorylation was completely blocked using the mTOR
inhibitor rapamycin. To evaluate if LKB1 inhibition by itself could promote the
hypertrophic signaling changes observed with HNE, LKB1 was depleted in adult rat
ventricular myocytes using siRNA. LKB1 knockdown did not replicate the effect of
HNE on hypertrophic signaling or affect HNE-stimulated RPS6 phosphorylation.
Thus, in adult cardiac myocytes HNE stimulates protein synthesis by activation of
mTORC1-p70S6K-RPS6 signaling most likely mediated by direct inhibition of AMPK.
Because HNE in the myocardium is commonly increased by stimuli that cause
pathologic hypertrophy, these findings suggest that therapies that prevent
activation of mTORC1-p70S6K-RPS6 signaling may be of therapeutic value.
|AMP-Activated Protein Kinases/antagonists & inhibitors/metabolism
[MESH]
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