Inhibition of endothelial- and neuronal-type, but not inducible-type, nitric oxide synthase by the oxidized cholesterol metabolite secosterol aldehyde: Implications for vascular and neurodegenerative diseases

Abstract

The cholesterol ozonolysis products secosterol-A and its aldolization product secosterol-B were recently detected in human atherosclerotic tissues and brain specimens, and have been postulated to play pivotal roles in the pathogenesis of atherosclerosis and neurodegenerative diseases. We examined several oxidized cholesterol metabolites including secosterol-A, secosterol-B, 25-hydroxycholesterol, 5β,6β-epoxycholesterol and 7-ketocholesterol for their effects on the activities of three nitric oxide synthases. In contrast to other oxidized metabolites, secosterol-A was found to be a potent inhibitor against the neuronal- and endothelial-type, but not the inducible-type nitric oxide synthase, with IC50 values of 22 ± 1 and 50 ± 5 µM, respectively. The calmodulin-binding regions of the neuronal- and endothelial-nitric oxide synthases contain lysine residues which are not present in the inducible-type nitric oxide synthase. Secosterol-A modifies proteins through the formation of a Schiff base with the lysine epsilon-amino group. It is possible that secosterol-A modifies lysine residues of constitutive nitric oxide synthases, leading to the inhibition of enzymatic activities. As nitric oxide is a critical signaling molecule in vascular function and in long-term potentiation, its reduced production through inhibition of constitutive nitric oxide synthases by secosterol-A may contribute to the development of atherosclerosis and memory impairment in particular neurodegenerative diseases.

Biochemical properties of cholesterol aldehyde secosterol and its derivatives

“…( 49 – 51 ) Secosterol-A, but not secosterol-B, reportedly inhibited endothelial- and neuronal-type NOS activities, probably mediated by adduct formations with lysine residues on these enzymes. ( 52 )…”

The Contribution of Singlet Oxygen to Insulin Resistance

“…Cholesterol oxidation generates two main aldehydic products, namely, cholesterol secosterol A and secosterol B [ 115 ]. Secosterol A potently inhibits endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS), but not iNOS [ 116 ], and should therefore make an important contribution to endothelial dysfunction and insulin resistance, since eNOS promotes insulin sensitivity while iNOS promotes insulin resistance in humans [ 117 ].…”

Chemical alterations and regulations of biomolecules in lifestyle-related diseases

“…31) Secosterol-A, but not secosterol-B, reportedly inhibited endothelial-and neuronal-type NOS activities, probably mediated by adduct formations with lysine residues on these enzymes. 32) The biochemical and biophysical properties of secosterols could be associated with their noxious activity on cells.…”