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Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies

2015; Impact Journals LLC; Volume: 6; Issue: 14 Linguagem: Inglês

10.18632/oncotarget.3979

1949-2553

Tyesha N. Burks, Ruth Marx, Laura Powell, Jasma Rucker, Djahida Bedja, Elisa Heacock, Barbara J. Smith, D. Brian Foster, David A. Kass, Brian O’Rourke, Jeremy Walston, Peter Abadir,

Mitochondrial Function and Pathology

// Tyesha N. Burks 1 , Ruth Marx 1 , Laura Powell 1 , Jasma Rucker 2 , Djahida Bedja 2 , Elisa Heacock 1 , Barbara J. Smith 3 , D. Brian Foster 2 , David Kass 2 , Brian O’Rourke 2 , Jeremy D. Walston 1 , Peter M. Abadir 1 1 Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine Baltimore, MD 21205, USA 2 Division of Cardiology, Johns Hopkins University School of Medicine Baltimore, MD 21205, USA 3 Cell Biology Imaging Facility, Johns Hopkins University School of Medicine Baltimore, MD 21205, USA Correspondence to: Peter M. Abadir, e-mail: pabadir1@jhmi.edu Keywords: aging, mitochondria, AT1R, inflammation, heart Received: April 4, 2015 Accepted: May 06, 2015 Published: May 18, 2015 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.