Not just correlative: a new pathway defines how an ALDH2 SNP contributes to atherosclerosis
Andrew A. Gibb, John W. Elrod
Andrew A. Gibb, John W. Elrod
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Commentary

Not just correlative: a new pathway defines how an ALDH2 SNP contributes to atherosclerosis

Abstract

Individuals with the rs671 SNP in the gene encoding aldehyde dehydrogenase 2 (ALDH2) are at increased risk of cardiovascular disease (CVD); however, it has been unclear if this mutation contributes to CVD development. In this issue of the JCI, Zhong et al. perform an elegant set of experiments that reveal a pathway wherein the ALDH2 rs671 mutant is phosphorylated by AMPK and translocates to the nucleus where it represses the transcription of a lysosomal H+ pump subunit that is critical for lipid degradation and foam cell formation, as occurs in atherosclerosis. The discovery of this pathway may explain how subjects harboring ALDH2 rs671 are at a greater risk for numerous other disease states and thereby provide new targets for therapeutic intervention.

Authors

Andrew A. Gibb, John W. Elrod

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Figure 1

An ALDH2 SNP contributes to atherosclerosis.

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An ALDH2 SNP contributes to atherosclerosis. In this issue of the JCI, Z...
In this issue of the JCI, Zhong et al. (5) identify a pathway that reveals how the ALDH2 rs671 SNP promotes atherosclerosis. (A) The low-density lipoprotein receptor (LDLR) physically interacts with aldehyde dehydrogenase 2 (ALDH2) and 5′ AMP-activated protein kinase (AMPK) to prevent AMPK-mediated phosphorylation and subsequent nuclear translocation of ALDH2. (B) The ALDH2 mutant protein (mALDH2 rs671 SNP) does not interact with LDLR, thereby removing the break on AMPK-mediated phosphorylation. Phospho-mALDH2 translocates to the nucleus and in an HDAC3-dependent fashion suppresses transcription of the lysosomal H+ pump subunit, ATP6V0E2. ATP6V0E2 is critical for lysosomal acidification and autophagic clearance of lipids. The loss of this critical pathway accelerates foam cell formation and atherosclerosis.