Reactive oxygen species homeostasis regulates 17β-estradiol mediation of low density lipoprotein receptor expression in macrophages

The steroid 17β-estradiol has emerged as having both beneficial and detrimental effects in relation to cardiovascular physiology. To provide clarity on the effect of 17β-estradiol on atherogenic process, we examined its regulatory role in LDL-receptor expression in macrophages. We determined if the previously reported 17β-estradiol-mediated reactive oxygen species (ROS) generation in macrophage has signaling consequences by examining the release of ROS, its homeostasis by antioxidant enzymes (SOD and γ-GCS) and the uptake of LDL in THP-1 derived macrophages. Also, we evaluated the antagonistic effect of progesterone on the processes. Estradiol exerted an upregulatory effect on native LDL-receptor expression, while progesterone exhibited a reverse effect despite subsequent exposure of cells to estradiol. Also, estradiol elicited ROS release, while progesterone attenuated the process. There was evidence that ROS homeostasis was essentially controlled by SOD and inhibition of SOD downregulates the expression of LDL-receptor. Estradiol also enhanced Ox-LDL or native LDL uptake, a process which was impaired by SOD inhibitor. These findings imply that estradiol acting alone may indeed favor atherogenic process by up-regulating LDL-receptor via induction of ROS signaling. However, in physiologic circumstances progesterone is present; therefore, its inhibitory effect may annul the process.