Abstract
Selenoprotein P (SeP), a liver-derived secretory protein, functions as a selenium supply protein in the body. SeP has been reported to be associated with insulin resistance in humans through serial analysis of gene expression. Recently, SeP has been found to inhibit vascular endothelial growth factor-stimulated cell proliferation in human umbilical vein endothelial cells, and impair angiogenesis in a mouse hind limb model. In this study, the role of SeP in ischemia/reperfusion (I/R) injury has been investigated. SeP knockout (KO) and littermate wild-type (WT) mice were subjected to 30 min of myocardial ischemia followed by 24 h of reperfusion. The myocardial infarct area/area at risk (IA/AAR), evaluated using Evans blue (EB) and 2,3,5-triphenyltetrazolium chloride (TTC) staining, was significantly smaller in SeP KO mice than in WT mice. The number of terminal de-oxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive nuclei was significantly lower in SeP KO mice than in WT mice. In addition, caspase-3 activation was reduced in SeP KO mice compared to that in WT mice. Furthermore, phosphoinositide 3-kinase/Akt and Erk levels were examined for the reperfusion injury salvage kinase (RISK) pathway. Interestingly, SeP KO significantly increased the phosphorylation of IGF-1, Akt, and Erk compared to that in WT mice after I/R. Finally, I/R-induced myocardial IA/AAR was significantly increased in SeP KO mice overexpressing SeP in the liver compared to other SeP KO mice. These results, together, suggest that inhibition of SeP protects the heart from I/R injury through upregulation of the RISK pathway.
Highlights
Ischemic heart disease is the leading cause of death in developed countries
Reperfusion itself can cause additional myocyte damage and death, which is typically defined as myocardial ischemia/reperfusion (I/R) injury
A brief episode of ischemia is known to be associated with myocardial resistance to lethal I/R injury, but these cardioprotective effects against I/R injury are abolished in patients with diabetes [6,7]
Summary
Ischemic heart disease is the leading cause of death in developed countries. Acute coronary syndrome (ACS) is the event that causes most deaths or new cases of heart failure [1]. Reperfusion itself can cause additional myocyte damage and death, which is typically defined as myocardial ischemia/reperfusion (I/R) injury. The insulin resistance and hyperinsulinemia in patients with type 2 diabetes are strong predictors of ischemic heart disease. In addition to elevating the incidence of ACS, diabetes is associated with increased cardiac morbidity and mortality following the recanalization of an occluded coronary artery compared to the non-diabetics, partly due to an increased size of myocardial infarction [5]. A brief episode of ischemia is known to be associated with myocardial resistance to lethal I/R injury, but these cardioprotective effects against I/R injury are abolished in patients with diabetes [6,7]. SeP serves as a hepatokine that contributes to the onset of hyperglycemia in type 2 diabetes by imparting insulin signal transduction in the liver and skeletal muscle [10]. The role of SeP during myocardial I/R has been investigated using SeP knockout (KO) mice
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