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Adaptation of cardiomyocytes to chronic hypoxia in cyanotic patients remains unclear. Mitochondrial biogenesis is enhanced in myocardium from cyanotic patients, which is possibly an adaptive response. Erythropoietin (EPO) in blood and its receptor (EPOR) on cardiomyocytes are upregulated by chronic hypoxia, suggesting that EPO-EPOR interaction is increased, which is inferred to positively regulate mitochondrial biogenesis through protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signalling pathway. H9c2 cardiomyocytes were exposed to hypoxia (1% O(2)) for 1 week and treated with different doses of recombinant human erythropoietin (rhEPO). Mitochondrial number, mitochondrial DNA (mtDNA) copy number and peroxisome proliferator activated receptor gamma coactivator alpha (PGC-1α) mRNA expression increased in a dose-dependent manner induced by rhEPO. Akt and eNOS were significantly phosphorylated by rhEPO. Both blocking Akt with Wortmannin and silencing eNOS expression with shRNA plasmid decreased the mtDNA copy number and PGC-1α mRNA expression induced by rhEPO. Blocking Akt was associated with the decreased phosphorylation of Akt and eNOS. RNA interference led to a reduction in the total and phosphorylated proteins of eNOS. Thus EPO enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia, at least partly through Akt/eNOS signalling, which might be an adaptive mechanism of cardiomyocytes associated with the increased EPO-EPOR interaction in patients with cyanotic congenital heart disease (CCHD).

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Oxidized low-density lipoprotein (ox-LDL)-induced endothelial insults plays an important role in the pathogenesis of atherosclerosis. Donepezil is a well-known acetylcholinesterase inhibitor with its primary application being the treatment of Alzheimer's disease. More recently, there has been increased interest in donepezil as an antiatherosclerosis treatment as it possesses a host of relevant and potentially beneficial properties. In the present study, we found that donepezil could reduce the expression of lectin-type oxidized low-density lipoprotein receptor-1 (LOX-1) in human aortic endothelial cells (HAECs). We found that donepezil could suppress the expression of intercellular adhesion molecule-1 (ICAM-1), which recruits monocytes to adhere to the endothelium, by more than half. Another key finding of our study is that donepezil could reduce the expression of tumor necrosis factor receptor-α (TNF-α) and interleukin-6 (IL-6) by more than half at both the mRNA and protein transcriptional levels. Donepezil also reduced the expression of tissue factor (TF), which is considerably upregulated in atherosclerotic lesions, by more than half. Finally, we turned our attention to the early growth response protein-1 (Egr-1) for its potential role in mediating the effects of donepezil. Through our Egr-1 overexpression experiment, we found that overexpression of Egr-1 almost completely abolished the effects of donepezil described above. Thus, the effects of donepezil are likely mediated through downregulation of Egr-1. These findings provide evidence that donepezil may exert protective effects against atherosclerosis.