Dr. Hage is Associate Professor of Medicine in the Division of Cardiovascular Disease, Director of Nuclear Cardiology at UAB, and Director of the Cardiac Care Unit at the BVAMC. He is also a member of the Vascular Biology and Hypertension Program.
In 2014, Dr. Hage and collaborators demonstrated that the effects of estrogen therapy on vascular inflammation are age dependent. In 2002, the Women’s Health Initiative (WHI) reported increased cardiovascular events in women treated with menopausal hormones compared to placebo. These results were in contrast to the well-established anti-inflammatory and vasoprotective effects of 17β-Estradiol (E2) seen in in vitro preparations, young adult laboratory animals, and observational studies in pre- and peri-menopausal women. Importantly, WHI enrolled older women than the observational studies.
The investigative team showed in a mouse model of vascular injury and in macrophages and vascular smooth muscle cells in culture that E2 inhibits inflammation in cells derived from young but not aged mice and in injured carotid arteries of young but not aged animals. This demonstration that the vasoprotective effects of E2 disappear with advancing age may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women, e.g, WHI, and pave the way for novel therapeutic interventions designed to preserve E2 responsiveness in aging vascular cells.
Abstract
Objective: 17β-Estradiol (E2) offers cardiovascular protection in young female animals and postmenopausal women. In contrast, randomized trials of menopausal hormones carried out in older women have shown harm or no cardiovascular benefit. We hypothesize that E2 effects on vascular inflammation are age-dependent.
Approach and Results: Young (10-wk) and aged (52-wk) female C57BL/6 mice were used as source for primary cultures of bone marrow-derived macrophages (BMMs) and vascular smooth muscle cells (VSMCs). E2 pre-treatment of cells derived from young mice attenuated C-reactive protein (CRP)-induced expression of inflammatory mediators. In contrast, E2 pre-treatment of cells from aged mice did not alter (BMMs) or paradoxically exaggerated (VSMCs) inflammatory mediator response to CRP. Using E2 receptor (ER)-knockout mice, we demonstrated that E2 regulates inflammatory response to CRP in BMMs via ERα and in VSMCs via ERβ. BMMs derived from aged (vs. young) mice expressed significantly less ERα mRNA and protein. A selective ligand of the novel ER GPR30 reproduced the E2 effects in BMMs and VSMCs. Unlike in young mice, E2 did not reduce neointima formation in ligated carotid arteries of aged CRP transgenic mice.
Conclusions: E2 attenuates inflammatory response to CRP in BMMs and VSMCs derived from young but not aged mice and reduces neointima formation in injured carotid arteries of young but not aged CRP transgenic mice. ERα expression in BMMs is greatly diminished with aging. These data suggest that vasoprotective effects of E2 are age-dependent and may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women.
Bio Sketch
Dr. Hage received his undergraduate and medical degrees with distinction from the American University of Beirut, Beirut, Lebanon. He then completed his internal medicine residency and cardiovascular disease fellowship at UAB. Dr. Hage did a post-doctoral research training with Dr. Suzanne Oparil sponsored by the Walter B. Frommeyer, Jr. Fellowship in Investigative Medicine.
His research has been funded by a Scientist Development Grant from the American Heart Association, a Merit Award from the Veterans' Affairs Administration, a research award from the UAB-UCSD O'Brien Core Center for Acute Kidney Injury Research, and investigator initiated grants from industry. Dr. Hage is a Fellow of the American College of Cardiology, a Fellow of the American Society of Hypertension, and a member of the Southern Society for Clinical Investigation. He currently serves as an Associate Editor of the Journal of Nuclear Cardiology and as the Education Committee Chair of the American College of Cardiology, Alabama Chapter.
Abstract
Objective: 17β-Estradiol (E2) offers cardiovascular protection in young female animals and postmenopausal women. In contrast, randomized trials of menopausal hormones carried out in older women have shown harm or no cardiovascular benefit. We hypothesize that E2 effects on vascular inflammation are age-dependent.
Approach and Results: Young (10-wk) and aged (52-wk) female C57BL/6 mice were used as source for primary cultures of bone marrow-derived macrophages (BMMs) and vascular smooth muscle cells (VSMCs). E2 pre-treatment of cells derived from young mice attenuated C-reactive protein (CRP)-induced expression of inflammatory mediators. In contrast, E2 pre-treatment of cells from aged mice did not alter (BMMs) or paradoxically exaggerated (VSMCs) inflammatory mediator response to CRP. Using E2 receptor (ER)-knockout mice, we demonstrated that E2 regulates inflammatory response to CRP in BMMs via ERα and in VSMCs via ERβ. BMMs derived from aged (vs. young) mice expressed significantly less ERα mRNA and protein. A selective ligand of the novel ER GPR30 reproduced the E2 effects in BMMs and VSMCs. Unlike in young mice, E2 did not reduce neointima formation in ligated carotid arteries of aged CRP transgenic mice.
Conclusions: E2 attenuates inflammatory response to CRP in BMMs and VSMCs derived from young but not aged mice and reduces neointima formation in injured carotid arteries of young but not aged CRP transgenic mice. ERα expression in BMMs is greatly diminished with aging. These data suggest that vasoprotective effects of E2 are age-dependent and may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women.
Bio Sketch
Dr. Hage received his undergraduate and medical degrees with distinction from the American University of Beirut, Beirut, Lebanon. He then completed his internal medicine residency and cardiovascular disease fellowship at UAB. Dr. Hage did a post-doctoral research training with Dr. Suzanne Oparil sponsored by the Walter B. Frommeyer, Jr. Fellowship in Investigative Medicine.
His research has been funded by a Scientist Development Grant from the American Heart Association, a Merit Award from the Veterans' Affairs Administration, a research award from the UAB-UCSD O'Brien Core Center for Acute Kidney Injury Research, and investigator initiated grants from industry. Dr. Hage is a Fellow of the American College of Cardiology, a Fellow of the American Society of Hypertension, and a member of the Southern Society for Clinical Investigation. He currently serves as an Associate Editor of the Journal of Nuclear Cardiology and as the Education Committee Chair of the American College of Cardiology, Alabama Chapter.
