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

Burks TN, Marx R, Powell L, Rucker J, Bedja D, Heacock E, Smith BJ, Foster DB, Kass D, O'Rourke B, Walston JD, Abadir PM - Oncotarget (2015)

Bottom Line: We show molecular distinction in the combined effect of aging and inflammation as compared to each independently.Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine Baltimore, MD 21205, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Expression of localized RAS receptors and downstream effectors in cardiac muscleA. Western blot analyses of cardiac protein extracts from young WT (yWT), aged WT (aWT), young IL-10−/− (yKO) and aged IL-10−/− (aKO) mice using antibodies against angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors and NAPDH oxidases (Nox) 2 and 4. Actin was used as a loading control. B. C. E. F. Relative expression was calculated for the Western blots displayed in (A.) in arbitrary units (AU). D. Ratio of the relative expression of AT1R (B.) to AT2R (C.). Data are means ± SEM. *p < 0.05; **p < 0.01; ***p > 0.001.
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Figure 1: Expression of localized RAS receptors and downstream effectors in cardiac muscleA. Western blot analyses of cardiac protein extracts from young WT (yWT), aged WT (aWT), young IL-10−/− (yKO) and aged IL-10−/− (aKO) mice using antibodies against angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors and NAPDH oxidases (Nox) 2 and 4. Actin was used as a loading control. B. C. E. F. Relative expression was calculated for the Western blots displayed in (A.) in arbitrary units (AU). D. Ratio of the relative expression of AT1R (B.) to AT2R (C.). Data are means ± SEM. *p < 0.05; **p < 0.01; ***p > 0.001.

Mentions: RAS is a key hormonal system whose dysregulation has been linked to aging, inflammation, mitochondrial dysfunction, and CVDs. We show that the expression of AT1R was highest in the cardiac muscle of the aged WT and increased in the young IL-10−/− mice as compared to the young WT and the aged IL-10−/− mice (Figure 1A–1B). Interestingly, the combined effect of aging and inflammation (aged IL-10−/−) decreased the expression of AT1R as compared to the aged WT mice (Figure 1B) which was unexpected given that AT1R levels correlate with negative outcomes in chronic inflammation [26]. In contrast, the levels of AT2R were similarly decreased in the aged WT, young IL-10−/− and aged IL-10−/− as compared to young WT mice (Figure 1A, 1C).


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

Burks TN, Marx R, Powell L, Rucker J, Bedja D, Heacock E, Smith BJ, Foster DB, Kass D, O'Rourke B, Walston JD, Abadir PM - Oncotarget (2015)

Expression of localized RAS receptors and downstream effectors in cardiac muscleA. Western blot analyses of cardiac protein extracts from young WT (yWT), aged WT (aWT), young IL-10−/− (yKO) and aged IL-10−/− (aKO) mice using antibodies against angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors and NAPDH oxidases (Nox) 2 and 4. Actin was used as a loading control. B. C. E. F. Relative expression was calculated for the Western blots displayed in (A.) in arbitrary units (AU). D. Ratio of the relative expression of AT1R (B.) to AT2R (C.). Data are means ± SEM. *p < 0.05; **p < 0.01; ***p > 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494917&req=5

Figure 1: Expression of localized RAS receptors and downstream effectors in cardiac muscleA. Western blot analyses of cardiac protein extracts from young WT (yWT), aged WT (aWT), young IL-10−/− (yKO) and aged IL-10−/− (aKO) mice using antibodies against angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors and NAPDH oxidases (Nox) 2 and 4. Actin was used as a loading control. B. C. E. F. Relative expression was calculated for the Western blots displayed in (A.) in arbitrary units (AU). D. Ratio of the relative expression of AT1R (B.) to AT2R (C.). Data are means ± SEM. *p < 0.05; **p < 0.01; ***p > 0.001.
Mentions: RAS is a key hormonal system whose dysregulation has been linked to aging, inflammation, mitochondrial dysfunction, and CVDs. We show that the expression of AT1R was highest in the cardiac muscle of the aged WT and increased in the young IL-10−/− mice as compared to the young WT and the aged IL-10−/− mice (Figure 1A–1B). Interestingly, the combined effect of aging and inflammation (aged IL-10−/−) decreased the expression of AT1R as compared to the aged WT mice (Figure 1B) which was unexpected given that AT1R levels correlate with negative outcomes in chronic inflammation [26]. In contrast, the levels of AT2R were similarly decreased in the aged WT, young IL-10−/− and aged IL-10−/− as compared to young WT mice (Figure 1A, 1C).

Bottom Line: We show molecular distinction in the combined effect of aging and inflammation as compared to each independently.Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine Baltimore, MD 21205, USA.

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.

No MeSH data available.


Related in: MedlinePlus