Previous evidence has indicated a beneficial role for
aldehyde dehydrogenase 2 (ALDH2) in suppressing
atherosclerotic plaque progression and instability. However, the underlying mechanism remains somewhat elusive. This study was designed to examine the effect of ALDH2 deficiency on high-
cholesterol diet-induced
atherosclerotic plaque progression and plaque vulnerability in
atherosclerosis-prone
ApoE knockout (
ApoE-/-) mice with a focus on foam cell formation in macrophages and senescence of vascular smooth muscle cells (VSMCs). Serum
lipid profile, plaque progression, and plaque vulnerability were examined in
ApoE-/- and ALDH2/
ApoE double knockout (ALDH2-/-
ApoE-/-) mice after high-
cholesterol diet intake for 8 weeks. ALDH2 deficiency increased the serum levels of
triglycerides while it decreased levels of total
cholesterol and
high-density lipoprotein cholesterol. Unexpectedly, ALDH2 deficiency reduced the plaque area by 58.9% and 37.5% in aorta and aortic sinus, respectively. Plaque instability was aggravated by ALDH2 deficiency along with the increased necrotic core size, decreased
collagen content, thinner fibrous cap area, decreased VSMC content, and increased macrophage content. In atherosclerotic lesions,
ALDH2 protein was located in both macrophages and VSMCs. Further results revealed downregulated ALDH2 expression in aorta of aged
ApoE-/- mice compared with young mice. However, in vitro study suggested that ALDH2 expression was upregulated in bone marrow-derived macrophages (BMDMs) with an opposite effect in VSMCs following 80 μg/ml
oxidized low-density lipoprotein (
oxLDL) treatment. Interestingly, ALDH2 deficiency displayed little effect in
oxLDL-induced foam cell formation from BMDMs, while ALDH2 knockdown by
siRNA and ALDH2 overexpression by
lentivirus infection promoted and retarded
oxLDL-induced VSMC senescence, respectively. Mechanistically, ALDH2 mitigated
oxLDL-induced overproduction of mitochondrial
reactive oxygen species (mROS) and activation of downstream p53/p21/p16 pathway. Clearance of mROS by
mitoTEMPO significantly reversed the promotive effect of ALDH2 knockdown on VSMC senescence. Taken together, our data revealed that ALDH2 deficiency suppressed
atherosclerotic plaque area while facilitating plaque instability possibly through accelerating mROS-mediated VSMC senescence. This article is part of a Special Issue entitled: Genetic and epigenetic regulation of aging and longevity edited by Jun Ren & Megan Yingmei Zhang.