Inhibition of ALDH2 by O-GlcNAcylation contributes to the hyperglycemic exacerbation of myocardial ischemia/reperfusion injury

Abstract

Although hyperglycemia is causally related to adverse outcomes after myocardial ischemia/reperfusion (I/R), the underlying mechanisms are largely unknown. Here, we investigated whether excessive O-linked-N-acetylglucosamine (O-GlcNAc) modification of acetaldehyde dehydrogenase 2 (ALDH2), an important cardioprotective enzyme, was a mechanism for the hyperglycemic exacerbation of myocardial I/R injury. Both acute hyperglycemia (AHG) and diabetes (DM)-induced chronic hyperglycemia increased cardiac dysfunction, infarct size and apoptosis index compared with normal saline (NS)+I/R rats (P<0.05). ALDH2 O-GlcNAc modification was increased whereas its activity was decreased in AHG+I/R and DM+I/R rats. High glucose (HG, 30mmol/L) markedly increased ALDH2 O-GlcNAc modification compared with Con group (5mmol/L) (P<0.05). ALDH2 O-GlcNAc modification was increased by 62.9% in Con+PUGNAc group whereas it was decreased by 44.1% in Con+DON group compared with Con group (P<0.05). Accordingly, ALDH2 activity was decreased by 18.1% in Con+PUGNAc group whereas it was increased by 17.9% in Con+DON group. Moreover, DON decreased levels of 4-hydroxy-2-nonenal (4-HNE), aldehydes, protein carbonyl accumulation and apoptosis index compared with HG+H/R group (P<0.05). Alda-1, a specific activator of ALDH2, significantly decreased ALDH2 O-GlcNAc modification and improved infarct size, apoptosis index and cardiac dysfunction induced by I/R combined with hyperglycemia. These findings demonstrate that ALDH2 O-GlcNAc modification is a key mechanism for the hyperglycemic exacerbation of myocardial I/R injury and Alda-1 has therapeutic potential for inducing cardioprotection.

Baicalin protects H9c2 cardiomyocytes against hypoxia/reoxygenation‐induced apoptosis and oxidative stress through activation of mitochondrial aldehyde dehydrogenase 2

“…Furthermore, we found that daidzin (an ALDH2 antagonist) abolished baicalin‐exhibited beneficent effects against H/R‐induced cytotoxicity and apoptosis in H9c2 cells, and Alda‐1 (an ALDH2 agonist) also reversed H/R‐induced cytotoxicity and apoptosis. These results were in accordance with these studies whereby the modulation of ALDH2 activity by daidzin or Alda‐1 could affect myocardial apoptosis caused by I/R or H/R injury in isolated hearts and in cells . These results suggested that enhancing of ALDH2 activity and expression mediated H/R injury and the protective effects of baicalin against H/R injury in H9c2 cells.…”

“…Emerging evidence show the beneficial impact of ALDH2 on ischaemia and reperfusion injuries . Hence, to further explore whether ALDH2 is involved in the protective effects of baicalin against H/R injury, we then demonstrate the effects of baicalin on ALDH2 level and activity in H9c2 cells.…”

“…Increasing evidence has revealed a cardioprotective role of ALDH2 in myocardial IR injury . In addition, experimental approaches using genetic overexpression or pharmacological activation of ALDH2 can protect against acute I/R injury and ischaemic ventricular dysfunction . We know that ALDH2 has been displayed as an anti‐apoptotic enzyme participated in oxidative stress‐induced cell apoptosis .…”

“…Emerging evidence show the beneficial impact of ALDH2 on ischaemia and reperfusion injuries. 11,24,25 Hence, to further explore whether ALDH2 is involved in the protective effects of baicalin against H/R injury, we then demonstrate the effects of baicalin on ALDH2 level and activity in H9c2 cells. As presented in Figure 2, H/R treatment obviously inhibited the levels of ALDH2 mRNA ( Figure 2A) and protein ( Figure 2B) in H9c2 cells, while these effects were reversed by pre-incubated with baicalin (10 μmol/L) ( Figure 2A Figure 2C).…”

Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA4‐Dependent CCN1 Secretion

“…We have a longstanding interest in the effects of ALDH2 and the cardiovascular system 24, 25, 26. We previously found that ALDH2 activation by Alda‐1 reduced the senescence phenotype in H9C2 cell lines 23.…”