Spirulina platensis, a water blue-green alga, has been associated with potent biological effects, which
might have important relevance in atheroprotection. We investigated whether S. platensis or
phycocyanobilin (PCB), its tetrapyrrolic chromophore, can activate atheroprotective heme oxygenase-1
(Hmox1), a key enzyme in the heme catabolic pathway responsible for generation of a potent
antioxidant bilirubin, in endothelial cells and in a mouse model of atherosclerosis. In vitro experiments
were performed on EA.hy926 endothelial cells exposed to extracts of S. platensis or PCB. In vivo studies
were performed on ApoE-deficient mice fed a cholesterol diet and S. platensis. The effect of these
treatments on Hmox1, as well as other markers of oxidative stress and endothelial dysfunction, was
then investigated. Both S. platensis and PCB markedly upregulated Hmox1 in vitro, and a substantial
overexpression of Hmox1 was found in aortic atherosclerotic lesions of ApoE-deficient mice fed
S. platensis. In addition, S. platensis treatment led to a significant increase in Hmox1 promoter activity in
the spleens of Hmox-luc transgenic mice. Furthermore, both S. platensis and PCB were able to modulate
important markers of oxidative stress and endothelial dysfunction, such as eNOS, p22 NADPH oxidase
subunit, and/or VCAM-1. Both S. platensis and PCB activate atheroprotective HMOX1 in endothelial cells
and S. platensis increased the expression of Hmox1 in aortic atherosclerotic lesions in ApoE-deficient
mice, and also in Hmox-luc transgenic mice beyond the lipid lowering effect. Therefore, activation of
HMOX1 and the heme catabolic pathway may represent an important mechanism of this food
supplement for the reduction of atherosclerotic disease.