Short- and long-term regulation of 3-hydroxy 3-methylglutaryl coenzyme A reductase by a 4-methylcoumarin

"""Dyslipidemia is one of the most significant risk factors for cardiovascular diseases. Cholesterol homeostasis. is regulated by both the receptor-mediated endocytosis of Low Density Lipoproteins by LDL. receptors and de novo cholesterol synthesis via the rate-limiting enzyme 3-hydroxy-3-methylglutaryl. coenzyme A reductase. Although statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase substrate. competitors, have revolutionized the management of cardiovascular diseases by lowering serum LDL,. their side effects range from myalgia to rhabdomyolysis. Treatment with antioxidant compounds could. represent an efficient alternative in the modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase. activity. Indeed it has already been demonstrated that the rise in reactive oxygen species levels. causes the complete dephosphorylation and, in turn activation of the enzyme.. Many coumarins and their derivatives have the special ability to scavenge reactive oxygen species or. show a lipid lowering potential.. Here we evaluated whether the coumarin, 4-methylesculetin could exert both the ability to scavenge. ROS and to modulate 3-hydroxy-3-methylglutaryl coenzyme A reductase in HepG2 cell line where the. enzyme activity dysregulation induced by reactive oxygen species has already been reported.. The antioxidant property of 4-methylesculetin led to the reduction of 3-hydroxy-3-methylglutaryl. coenzyme A reductase activation state through the increase of the enzyme phosphorylation. In addition,. this coumarin showed the ability to modulate 3-hydroxy-3-methylglutaryl coenzyme A reductase. protein levels both by transcriptional and degradational events independent of its antioxidant activity."""