Zhao, Junyun

While the strong connection between oxidative stress and atherosclerosis has many to hypothesize that antioxidant therapy may be viable therapeutic target in combating progression of atherosclerosis, numerous clinical trials of antioxidant interventions that scavenge multiple reactive oxygen species have been negative. Here, we test the hypothesis that overexpression of catalase—an enzyme which selectively degrades H 2 O 2 —plays a protective role against the initiation and expansion of calcific lesions in advanced atherosclerotic plaques. In vitro, we used aortic smooth muscle cells (SMC) from Ldlr -/- ApoB 100/100 (LA) mice that were either wild-type for human catalase (LA-Cat 0/0 ) or overexpressing human catalase (LA-Cat Tg/0 ). After treatment with BMP2 or TNFα for 24 hours, we found that catalase-overexpressing VSMCs had modest reductions in TNFα-induced inflammatory markers but paradoxical increases in mRNA levels of BMP2-induced osterix and the SMAD-specific target ID1. To determine if these effects were conserved in vivo, we analyzed aortic tissue from LA mice fed a Western diet for 3 or 12 months. Surprisingly—and unlike our cell-based experiments—aorta from LA-Cat Tg/0 tended to have higher expression of inflammatory markers compared to their LA-Cat 0/0 littermates. Similarly, expression of osterix was increased in LA-Cat Tg/0 mice compare to their LA-Cat 0/0 littermates, which was also associated with an increase in intimal plaque calcification. Collectively, these data strongly suggest that systemically overexpression of catalase (a close parallel to systemic administration of a selective H 2 O 2 -scavenging antioxidant) does not result in molecular, histopathological, or functional benefits in large arteries from hypercholesterolemic mice. Future studies aimed at characterizing the complex interplay between reactive oxygen species and specific intracellular signaling pathways are an essential next step to understanding the role of endogenous reactive oxygen species in the pathogenesis of atherosclerotic vascular disease.