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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

Effects of losartan treatment on downstream effectors of AT1R and antioxidantsWestern blot analyses of cardiac protein extracts from aged WT (aWT) A., young IL-10−/− (yKO) E., and aged IL-10−/− (aKO) I. mice with (+L) or without losartan treatment using antibodies against NADPH oxidases (Nox) 2 and 4 and Catalase (Cat). Actin was used as a loading control. Relative expression was calculated for the Western blots displayed in arbitrary units (AU) for aWT B–D., yKO F–H. and aKO J–L. Data are means ± SEM. *p < 0.05, **p < 0.01.
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Figure 5: Effects of losartan treatment on downstream effectors of AT1R and antioxidantsWestern blot analyses of cardiac protein extracts from aged WT (aWT) A., young IL-10−/− (yKO) E., and aged IL-10−/− (aKO) I. mice with (+L) or without losartan treatment using antibodies against NADPH oxidases (Nox) 2 and 4 and Catalase (Cat). Actin was used as a loading control. Relative expression was calculated for the Western blots displayed in arbitrary units (AU) for aWT B–D., yKO F–H. and aKO J–L. Data are means ± SEM. *p < 0.05, **p < 0.01.

Mentions: Losartan treatment (Los) reduced the expression levels of AT1R in the aged WT (Figure 4A–4B), young IL-10−/−(Figure 4E–4F), and aged IL-10−/− (Figure 4I–4J) mice as compared to their respective placebo-treated, age- and genotype-matched counterparts. While Los did not change the AT2R expression in aged WT (Figure 4A, 4C) and young IL-10−/− mice (Figure 4E, 4G), it decreased AT2R expression in the aged IL-10−/− mice (Figure 4I, 4K). Nonetheless, the AT1R:AT2R was decreased in all losartan-treated groups as compared to their placebo-treated counterparts (Figure 4D, 4H, 4L). We next measured the effects of Los on the downstream effectors of AT1R. Los decreased Nox2 levels in the young (Figure 5E–5F) and old (Figure 5I–5J) IL-10−/− mice, but had no effect on levels in aged WT (Figure 5A–5B). Levels of Nox4 were decreased in the aged WT (Figure 5A, 5C), but unchanged in the young (Figure 5E, 5G) and aged IL-10−/− mice (Figure 5I, 5K) with treatment. Los had a differential impact on the downstream effectors by decreasing the specific Nox proteins that were differentially increased in aging versus inflammation.


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)

Effects of losartan treatment on downstream effectors of AT1R and antioxidantsWestern blot analyses of cardiac protein extracts from aged WT (aWT) A., young IL-10−/− (yKO) E., and aged IL-10−/− (aKO) I. mice with (+L) or without losartan treatment using antibodies against NADPH oxidases (Nox) 2 and 4 and Catalase (Cat). Actin was used as a loading control. Relative expression was calculated for the Western blots displayed in arbitrary units (AU) for aWT B–D., yKO F–H. and aKO J–L. Data are means ± SEM. *p < 0.05, **p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Effects of losartan treatment on downstream effectors of AT1R and antioxidantsWestern blot analyses of cardiac protein extracts from aged WT (aWT) A., young IL-10−/− (yKO) E., and aged IL-10−/− (aKO) I. mice with (+L) or without losartan treatment using antibodies against NADPH oxidases (Nox) 2 and 4 and Catalase (Cat). Actin was used as a loading control. Relative expression was calculated for the Western blots displayed in arbitrary units (AU) for aWT B–D., yKO F–H. and aKO J–L. Data are means ± SEM. *p < 0.05, **p < 0.01.
Mentions: Losartan treatment (Los) reduced the expression levels of AT1R in the aged WT (Figure 4A–4B), young IL-10−/−(Figure 4E–4F), and aged IL-10−/− (Figure 4I–4J) mice as compared to their respective placebo-treated, age- and genotype-matched counterparts. While Los did not change the AT2R expression in aged WT (Figure 4A, 4C) and young IL-10−/− mice (Figure 4E, 4G), it decreased AT2R expression in the aged IL-10−/− mice (Figure 4I, 4K). Nonetheless, the AT1R:AT2R was decreased in all losartan-treated groups as compared to their placebo-treated counterparts (Figure 4D, 4H, 4L). We next measured the effects of Los on the downstream effectors of AT1R. Los decreased Nox2 levels in the young (Figure 5E–5F) and old (Figure 5I–5J) IL-10−/− mice, but had no effect on levels in aged WT (Figure 5A–5B). Levels of Nox4 were decreased in the aged WT (Figure 5A, 5C), but unchanged in the young (Figure 5E, 5G) and aged IL-10−/− mice (Figure 5I, 5K) with treatment. Los had a differential impact on the downstream effectors by decreasing the specific Nox proteins that were differentially increased in aging versus inflammation.

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