Selenoprotein expression is essential in endothelial cell development and cardiac muscle function

Abstract

LoxP-Cre technology was used to remove the selenocysteine tRNA gene, trsp, in either endothelial cells or myocytes of skeletal and heart muscle to elucidate the role of selenoproteins in cardiovascular disease. Loss of selenoprotein expression in endothelial cells was embryonic lethal. A 14.5-day-old embryo had numerous abnormalities including necrosis of the central nervous system, subcutaneous hemorrhage and erythrocyte immaturity. Loss of selenoprotein expression in myocytes manifested no apparent phenotype until about day 12 after birth. Affected mice had decreased mobility and an increased respiratory rate, which proceeded rapidly to death. Pathological analysis revealed that mice lacking trsp had moderate to severe myocarditis with inflammation extending into the mediastinitis. Thus, ablation of selenoprotein expression demonstrated an essential role of selenoproteins in endothelial cell development and in proper cardiac muscle function. The data suggest a direct connection between the loss of selenoprotein expression in these cell types and cardiovascular disease.

Loss of housekeeping selenoprotein expression in mouse liver modulates lipoprotein metabolism

“…Earlier studies have suggested a role of selenium [20] and/or selenoproteins in cardiovascular disorders [21] and reports indicate that cholesterol levels increase in selenium deficient animals compared to adequate selenium fed animals [22]. Our studies suggest that these effects are most likely executed through a select group of selenoproteins as our mouse models have shown that the loss of Sec tRNA [Ser]Sec elicits similar conditions, even under selenium sufficient diets.…”

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

“…Germline disruption of trsp in mice leads to early embryonic lethality (98). Tissue-specific loss of trsp in endothelial cells, skin cells, osteochondroprogenitor cells, or neurons leads to a panoply of defects that share such features as growth retardation, degeneration, and premature death (99)(100)(101)(102)(103). Liverspecific loss of trsp disrupts selenoprotein synthesis and causes liver necrosis and death (104).…”

Selective Restoration of the Selenoprotein Population in a Mouse Hepatocyte Selenoproteinless Background with Different Mutant Selenocysteine tRNAs Lacking Um34

“…This model has also been used to examine other aspects of the role of selenoproteins in health (51,52). Our floxed trsp model using loxP/ Cre technology allowing targeted removal of trsp in specific tissues or organs has been used to show that selenoproteins play a role in endothelial development and heart disease prevention (26), proper liver function (27), neuronal function, 9 and in skin function and development.…”

“…The targeted removal of floxed trsp in defined cell types using transgenic mice with tissue-specific expression of Cre recombinase permitted some study of the effects of selenoprotein loss in specific tissues and organs in the absence of endogenous trsp. However, the resulting animals have a variety of defects, including embryonic mortality or early adult death (26), thus restricting the use of these models for studying the role of selenium and selenoproteins in health.…”