Drug targeting of estrogen receptor signaling in the cardiovascular system: preclinical and clinical studies.
Atherosclerosis and associated coronary heart disease events have lower prevalence in women than in men, especially during young adult years. Although multiple lines of evidence suggest that estrogens contribute to this difference, the efficacy of hormone replacement therapy for the prevention of cardiovascular disease in postmenopausal women is controversial. The protective action of estrogen in the cardiovascular system appears to be mediated indirectly by an effect on serum lipoprotein and triglyceride profiles and on the expression of coagulant and fibrinolytic proteins, and by a direct effect on the vessel wall itself. Estrogen has both rapid effects involving alteration of membrane ionic permeability and activation of membrane-bound enzymes and increases in endothelial cell nitric oxide synthase activity, as well as longer-term effects on gene expression that are mediated, at least in part, by the ligand-activated transcription factors, estrogen receptor alpha and beta. Compounds with pure antiestrogenic activity and selective estrogen receptor modulators that regulate estrogen receptor function in a tissue-specific manner have been developed in an attempt to achieve the cardioprotective effects of estrogens while minimizing the undesirable risks associated with hormone replacement therapy (e.g., endometrial and breast cancer). In this review, we will discuss recent developments on the mechanisms of estrogen action in the cardiovascular system. The results of clinical trials testing the long-term efficacy of hormone replacement therapy for the treatment of cardiovascular disease will also be discussed.
Laboratory of Vascular Biology, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia, Spanish Council for Scientific Research, Valencia, Spain.
Silvia M
SM
Sanz-González
Antonio
A
Cano
M A
MA
Valverde
Carlos
C
Hermenegildo
Vicente
V
Andrés
D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002986:Clinical Trials as Topic; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000502:physiology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D004967:Estrogens; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators