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Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation.

ABSTRACT: 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 17?-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-?. Caspase 6, STAT3, and CD11b increased in the Late group, while tissue inhibitor of metalloproteinase 2, MMP14, and collagen I ?1 were decreased. MADD and fibronectin were increased in both Ovx and Late. TNF-? 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-? and iNOS, may be involved in some of the deleterious effects of delayed E2 administration seen in human studies.

SUBMITTER: Pechenino AS

PROVIDER: S-EPMC3180739 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation.

Pechenino Angela S AS Lin Li L Mbai Fiona N FN Lee Alison R AR He Xian-Min XM Stallone John N JN Knowlton A A AA

Physiological genomics 20110712 18

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 slo ...[more]

PMID: 21750230

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Project description:BackgroundThe three-layered meninges cover and protect the central nervous system and form the interface between cerebrospinal fluid and the brain. They are host to a lymphatic system essential for maintaining fluid dynamics inside the cerebrospinal fluid-filled subarachnoid space and across the brain parenchyma via their connection to glymphatic structures. Meningeal fibroblasts lining and traversing the subarachnoid space have direct impact on the composition of the cerebrospinal fluid through endocytotic uptake as well as extensive protein secretion. In addition, the meninges are an active site for immunological processes and act as gatekeeper for immune cells entering the brain. During aging in mice, lymphatic drainage from the brain is less efficient contributing to neurodegenerative processes. Aging also affects the immunological status of the meninges, with increasing numbers of T cells, changing B cell make-up, and altered macrophage complement.MethodsWe employed RNASeq to measure gene expression and to identify differentially expressed genes in meninges isolated from young and aged mice. Using Ingenuity pathway, GO term, and MeSH analyses, we identified regulatory pathways and cellular functions in meninges affected by aging.ResultsAging had profound impact on meningeal gene expression. Pathways related to innate as well as adaptive immunity were affected. We found evidence for increasing numbers of T and B lymphocytes and altered activity profiles for macrophages and other myeloid cells. Furthermore, expression of pro-inflammatory cytokine and chemokine genes increased with aging. Similarly, the complement system seemed to be more active in meninges of aged mice. Altered expression of solute carrier genes pointed to age-dependent changes in cerebrospinal fluid composition. In addition, gene expression for secreted proteins showed age-dependent changes, in particular, genes related to extracellular matrix composition and organization were affected.ConclusionsAging has profound effects on meningeal gene expression; thereby affecting the multifaceted functions meninges perform to maintain the homeostasis of the central nervous system. Thus, age-dependent neurodegenerative processes and cognitive decline are potentially in part driven by altered meningeal function.

Dataset Information

Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation.

Publications

Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation.

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