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Title: 17B-estradiol reduces Cav1.2 channel abundance and attenuates Ca2+-dependent contractions in coronary arteries

item HILL, BRENT J.F. - University Of Central Arkansas
item DALTON, ROBIN - University Of Central Arkansas
item JOSEPH, BINY - University Arkansas For Medical Sciences (UAMS)
item THAKALI, KESHARI - University Arkansas For Medical Sciences (UAMS)
item RUSCH, NANCY - University Arkansas For Medical Sciences (UAMS)

Submitted to: Pharmacology Research and Perspectives
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/4/2017
Publication Date: 10/1/2017
Citation: Hill, B., Dalton, R.J., Joseph, B.K., Thakali, K.M., Rusch, N.J. 2017. 17B-estradiol reduces Cav1.2 channel abundance and attenuates Ca2+-dependent contractions in coronary arteries. Pharmacology Research and Perspectives. 5(5): e00358.

Interpretive Summary: Before menopause, women have significantly lower rates of cardiovascular disease compared to men, but after menopause, women are at much higher risk of developing cardiovascular disease. While it is thought that the hormone estrogen is important in cardio-protection in women, the underlying mechanisms are not well understood. Notably, foods rich in soy contain so-called "phytoestrogens," which are plant molecules that have some properties in tissues that mimic estrogen, when at high enough concentrations in the blood. Many infant formulas—especially in the past—contain soy, and many adults and children consume soy-containing foods. The role of phytoestrogens in cardiovascular function remain to be fully elaborated, and the specific pathways involved in regulation of blood vessel function by estrogens are not fully known. This manuscript describes studies that explored whether estrogen can alter the amount and function of calcium channels in coronary arteries from female pigs. Estrogen treatment reduced calcium channel in these vessels, suggesting a potential mechanism for how estrogen is cardio-protective in pre-menopausal women. This study opens the door for further studies to determine if a diet high in phytoestrogens, like those found in soy, could be cardio-protective or have cardiovascular effects in children and adults.

Technical Abstract: One mechanism by which the female sex may protect against elevated coronary vascular tone is inhibition of Ca2+ entry into arterial smooth muscle cells (ASMCs). In vitro findings confirm that high estrogen concentrations directly inhibit voltage-dependent Cav1.2 channels in coronary ASMCs. For this study, we hypothesized that the nonacute, in vitro exposure of coronary arteries to a low concentration of 17B-estradiol (17BE) reduces the expression of Cav1.2 channel proteins in coronary ASMCs. Segments of the right coronary artery obtained from sexually mature female pigs were mounted for isometric tension recording. As expected, our results indicate that high concentrations (>=10 umol/L) of 17BE acutely attenuated Ca2+-dependent contractions to depolarizing KCl stimuli. Interestingly, culturing coronary arteries for 24 h in a 10,000-fold lower concentration (1 nmol/L) of 17BE also attenuated KCl-induced contractions and reduced the contractile response to the Cav1.2 agonist, FPL64176, by 50%. Western blots revealed that 1 nmol/L 17BE decreased protein expression of the pore-forming a 1C subunit (Cav a) of the Cav1.2 channel by 35%; this response did not depend on an intact endothelium. The 17BE-induced loss of Cav a protein in coronary arteries was prevented by the estrogen ER a/ER B antagonist, ICI 182,780, whereas the GPER antagonist, G15, did not prevent it. There was no effect of 1 nmol/L 17BE on Cav a transcript expression. We conclude that 17BE reduces Cav1.2 channel abundance in isolated coronary arteries by a posttranscriptional process. This unrecognized effect of estrogen may confer physiological protection against the development of abnormal Ca2+-dependent coronary vascular tone.