G-protein-coupled estrogen receptor as a new therapeutic target for treating coronary artery disease

Abstract

Coronary heart disease (CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; however, a significant array of potentially debilitating side effects continues to limit their use. Moreover, recent clinical trials have indicated that long-term postmenopausal estrogen therapy may actually be detrimental to cardiovascular health. An exciting new development is the finding that the more recently discovered G-protein-coupled estrogen receptor (GPER) is expressed in coronary arteries-both in coronary endothelium and in smooth muscle within the vascular wall. Accumulating evidence indicates that GPER activation dilates coronary arteries and can also inhibit the proliferation and migration of coronary smooth muscle cells. Thus, selective GPER activation has the potential to increase coronary blood flow and possibly limit the debilitating consequences of coronary atherosclerotic disease. This review will highlight what is currently known regarding the impact of GPER activation on coronary arteries and the potential signaling mechanisms stimulated by GPER agonists in these vessels. A thorough understanding of GPER function in coronary arteries may promote the development of new therapies that would help alleviate CHD, while limiting the potentially dangerous side effects of estrogen therapy.

Keywords: Atherosclerosis; Coronary arteries; Estrogen; G-1; G-protein-coupled estrogen receptor.

Figure 1

Summary of proposed mechanisms mediating the effects of G-protein-coupled estrogen receptor activation in coronary arteries. GPER is activated by 17β-estradiol and the selective agonist, G-1. In addition, selective estrogen receptor modulators (e.g., raloxifene, tamoxifen) and selective estrogen receptor down regulators (e.g., ICI182,780) also appear to be agonists for GPER. GPER activation induces an endothelium-independent relaxation of coronary artery smooth muscle mediated by the large-conductance, calcium-activated potassium channel. In addition, GPER activation can stimulated release of NO from coronary endothelial cells to relax these arteries. Besides this vasodilatory effect, GPER activation can attenuate proliferation and migration of coronary artery smooth muscle cells by inhibiting signaling via the ERK1/2 and Akt pathways. GPER: G-protein-coupled estrogen receptor; SERMs: Selective estrogen receptors modulators; SERD: Estrogen receptor down regulator; ERK: Extracellular signal-regulated protein kinase.