Impact of aging vs. estrogen loss on cardiac gene expression: Estrogen replacement and inflammation
Cellular and Molecular Cardiology, Department of Medicine, University of California, Davis, CA, United States; Department of Medical Pharmacology, University of California, Davis, CA, United States; VA Northern California Health Care System, Mather, CA, United States; Department of Physiology, Second Military Medical University, Shanghai, China; Institute of Tropical Medicine and Infectious Diseases, University of Nairobi, Nairobi, Kenya; Shanghai Rongjian Biotechnology Co, Ltd, Shanghai, China; Department of Physiology and Pharmacology, School of Veterinary Medicine, Texas A and M, College Station, TX, United States
Despite an abundance of evidence to the contrary from animal studies, large clinical trials on humans have shown that estrogen administered to postmenopausal women increases the risk of cardiovascular disease. However, timing may be everything, as estrogen is often administered immediately after ovariectomy (Ovx) in animal studies, while estrogen administration in human studies occurred many years postmenopause. This study investigates the discrepancy by administering 17β-estradiol (E2) in a slow-release capsule to Norway Brown rats both immediately following Ovx and 9 wk post-Ovx (Late), and studying differences in gene expression between these two groups compared with age-matched Ovx and sham-operated animals. Two different types of microarray were used to analyze the left ventricles from these groups: an Affymetrix array (n = 3/group) and an inflammatory cytokines and receptors PCR array (n = 4/group). Key genes were analyzed by Western blotting. Ovx without replacement led to an increase in caspase 3, caspase 9, calpain 2, matrix metalloproteinase (MMP)9, and TNF-α. Caspase 6, STAT3, and CD11b increased in the Late group, while tissue inhibitor of metalloproteinase 2, MMP14, and collagen I α1 were decreased. MADD and fibronectin were increased in both Ovx and Late. TNF-α and inducible nitric oxide synthase (iNOS) protein levels increased with Late replacement. Many of these changes were prevented by early E2 replacement. These findings suggest that increased expression of inflammatory genes, such as TNF-α and iNOS, may be involved in some of the deleterious effects of delayed E2 administration seen in human studies.
calpain 2; caspase 3; caspase 6; caspase 9; CD11b antigen; collagen; collagen I alpha1; estradiol; estrogen; fibronectin; gelatinase B; inducible nitric oxide synthase; matrix metalloproteinase 14; STAT3 protein; tissue inhibitor of metalloproteinase 4; tumor necrosis factor alpha; unclassified drug; aging; animal experiment; apoptosis; article; cardiovascular disease; cardiovascular function; concentration (parameters); controlled study; depletion; drug capsule; drug release; esterogen loss; estrogen therapy; female; gene expression; heart left ventricle; inflammation; microarray analysis; nonhuman; ovariectomy; polymerase chain reaction; priority journal; rat; Western blotting; Aging; Animals; Apoptosis; Blotting, Western; Estrogen Replacement Therapy; Estrogens; Extracellular Matrix; Female; Gene Expression Regulation; Humans; Inflammation; Models, Biological; Myocardium; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Rats; Rats, Inbred BN; Signal Transduction; Animalia; Rattus norvegicus