title: Combined effects of aging and inflammation on renin-angiotensin  system mediate mitochondrial dysfunction and phenotypic  changes in cardiomyopathies.
abstract: Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT(1)R, AT(2)R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT(1)R:AT(2)R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT(1)R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently.
authors.affiliation: Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine Baltimore, MD 21205, USA.
authors.forename: Tyesha N
authors.initials: TN
authors.lastname: Burks
authors.forename: Ruth
authors.initials: R
authors.lastname: Marx
authors.forename: Laura
authors.initials: L
authors.lastname: Powell
authors.forename: Jasma
authors.initials: J
authors.lastname: Rucker
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Elisa
authors.initials: E
authors.lastname: Heacock
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Smith
authors.forename: D Brian
authors.initials: DB
authors.lastname: Foster
authors.forename: David
authors.initials: D
authors.lastname: Kass
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Walston
authors.forename: Peter M
authors.initials: PM
authors.lastname: Abadir
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000473:pathology*; D010641:Phenotype; D012084:Renin-Angiotensin System / Q000502:physiology*