Lack of Antioxidant Genes Promoter Reduces Vascular Disease Risk

A protein that activates anti-inflammatory and antioxidant genes does not protect against development of atherosclerosis, a finding that surprised and disappointed cardiovascular disease researchers.

Increasing the expression of the protein nuclear factor (erythroid-derived 2)-like 2 (NF-E2–related factor 2 or Nrf2), has shown promise in treating some types of inflammatory diseases such as cancer and diabetes. To test its possible application in cardiovascular diseases, investigators at the University of California, Los Angeles (USA) developed strains of mice that lacked either one or both alleles for the Nrf2 gene. Various parameters related to lipid metabolism and development of atherosclerosis were determined in these heterozygous (Het) and knockout (KO) populations and compared to those in a wild-type control group. It was expected that lack of Nrf2 would be detrimental to that group of mice.

Results published in the January 2011 issue of the journal Arteriosclerosis, Thrombosis and Vascular Biology revealed that while KO mice exhibited decreased levels of antioxidant genes with evidence of increased reactive oxygen species generation compared with wild-type controls, KO males actually exhibited 47% and 53% reductions in the degree of aortic atherosclerosis compared with HET or wild-type littermates, respectively. In addition, KO mice exhibited atherosclerotic plaques characterized by a lesser macrophage component and decreased foam cell formation in an in vitro lipid-loading assay.
These unexpected results – that reduced Nrf2 expression was beneficial - were at least partially explained by findings that KO mice also had lower levels of liver cholesterol and reduced expression of lipogenic genes.

"We were very surprised at the finding," said senior author Dr. Jesus Araujo, professor of environmental cardiology at the University of California, Los Angeles. "In fact, the atherosclerosis-producing factors were greater than the antioxidant benefits. The development of novel antioxidant therapies is quite important, and this research may help shed light on why treatments affecting this protein may not be as effective as we thought."

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