Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque

Abstract

Previous studies demonstrated that aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which eliminates ALDH2 activity down to 1%-6%, is a susceptibility gene for coronary disease. Here we investigated the underlying mechanisms based on our prior clinical and experimental studies. Male apoE−/− mice were transfected with GFP, ALDH2-overexpression and ALDH2-RNAi lentivirus respectively (n=20 each) after constrictive collars were placed around the right common carotid arteries. Consequently, ALDH2 gene silencing led to an increased en face plaque area, more unstable plaque with heavier accumulation of lipids, more macrophages, less smooth muscle cells and collagen, which were associated with aggravated inflammation. However, ALDH2 overexpression displayed opposing effects. We also found that ALDH2 activity decreased in atherosclerotic plaques of human and aged apoE−/− mice. Moreover, in vitro experiments with human umbilical vein endothelial cells further illustrated that, inhibition of ALDH2 activity resulted in elevating inflammatory molecules, an increase of nuclear translocation of NF-κB, and enhanced phosphorylation of NF-κB p65, AP-1 c-Jun, Jun-N terminal kinase and p38 MAPK, while ALDH2 activation could trigger contrary effects. These findings suggested that ALDH2 can influence plaque development and vulnerability, and inflammation via MAPK, NF-κB and AP-1 signaling pathways.

HSP90 inhibition suppresses inflammatory response and reduces carotid atherosclerotic plaque formation in ApoE mice

“…Existing evidences indicate that inflammation significantly affects in plaque instability. IL‐6 and ICAM‐1 are putative markers of inflammation in identify vulnerable plaques . In our present experiment, we observed changes in IL‐6 and ICAM‐1 expression, which were positively correlated with HSP90 expression.…”

Urinary Excretion of N1-methyl-2-pyridone-5-carboxamide and N1-methylnicotinamide in Renal Transplant Recipients and Donors

“…Smoking and alcohol consumption are well-known factors [37,38] that showed an inverse association with urinary 2Py/N 1 -MN in RTR. Diabetes and inflammatory mediators [37], including hs-CRP [39,40], have also been implicated in AOX1 activity, as well as HDL-cholesterol-levels via interaction of AOX1 with the ATP-binding cassette transporter A1 (ABCA1) which is a regulator of HDL metabolism [41,42]. Surprisingly, medication use did not appear to affect urinary 2Py/N 1 -MN in RTR, despite the significant function of AOX1 in metabolizing xenobiotics.…”

Aldehyde dehydrogenase 2 Glu504Lys variant predicts a worse prognosis of acute coronary syndrome patients

“…As to the underlying mechanisms of how the variant influenced the prognosis of ACS, it might be related to the effect of ALDH2 on detoxification of toxic aldehydes, inhibition of oxidative stress and inflammation, and so on. [6][7][8][9][10][11][12][13][14][15] In animal models of MI, enhancement of ALDH2 activity by Alda-1 or overexpression of ALDH2 could significantly alleviate ischaemia/reperfusion injury, reduce infarct size of heart, and improve ventricular function and heart failure outcome after MI or in post-MI cardiomyopathy, via reducing the toxic effects of aldehydic overload, inhibiting reactive oxygen species generation and regulating autophagy. [8][9][10][11][12][13] Moreover, ALDH2 performed an important function on alleviating cardiomyocytes apoptosis and myocardial senescence through protecting mitochondrial function and correction of autophagy.…”