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Age-associated vascular inflammation promotes monocytosis during atherogenesis.

Du W, Wong C, Song Y, Shen H, Mori D, Rotllan N, Price N, Dobrian AD, Meng H, Kleinstein SH, Fernandez-Hernando C, Goldstein DR - Aging Cell (2016)

Bottom Line: In addition, in vitro cultures showed that aging enhanced the production of osteopontin by vascular smooth muscle cells.Functionally, aged atherosclerotic aortas displayed higher monocyte chemotaxis than young aortas.Hence, our study has revealed that aging induces metabolic dysfunction and enhances vascular inflammation to promote a peripheral monocytosis and macrophage accumulation within the atherosclerotic aorta.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

No MeSH data available.


Related in: MedlinePlus

Aging induces a peripheral monocytosis and increased macrophage numbers within the aorta. (A–B) Young (2 months of age) and aged (12 months of age) male Ldlr−/− mice were lethally irradiated and then reconstituted i.v. with 1 × 107 bone marrow cells from age‐matched or age‐mismatched Ldlr−/− donor mice. The mice were rested for 2 months and then fed a HFD for 2 months. Atherosclerotic lesion assessment was determined by lesion size in the aortic root by H&E. Blue scale bar = 100 μm. *P < 0.05; **P < 0.001 (t‐test). (C–D) Young (2 months) and aged (12 months) male Ldlr−/− mice were placed on a HFD diet for the indicated time. At weekly intervals, peripheral blood was obtained and peripheral blood mononuclear cells were isolated. The cells were stained with fluorescently labeled monoclonal antibodies to assess patrolling monocytes CD115+, Ly6clo cells) (C) and inflammatory monocytes (CD115+, Ly6chi cells) (D). N = 15–20 mice group, error bars = SEM. Each data point per time interval was significantly different between the young and aged groups (P < 0.001, t‐test). (E) The aortas of Ldlr−/− young and aged mice maintained on a chow diet or given a HFD for 1 month were harvested, digested and their cellular suspensions were obtained. The cells were stained with fluorescently tagged monoclonal antibodies and fluorescent data acquired via flow cytometry. Macrophages defined as CD11b+, F4/80+GR1−. *P < 0.01 (t‐test). (F) As per E but mice were administered BrdU in the drinking water up to 1 week prior to tissue harvest.
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acel12488-fig-0005: Aging induces a peripheral monocytosis and increased macrophage numbers within the aorta. (A–B) Young (2 months of age) and aged (12 months of age) male Ldlr−/− mice were lethally irradiated and then reconstituted i.v. with 1 × 107 bone marrow cells from age‐matched or age‐mismatched Ldlr−/− donor mice. The mice were rested for 2 months and then fed a HFD for 2 months. Atherosclerotic lesion assessment was determined by lesion size in the aortic root by H&E. Blue scale bar = 100 μm. *P < 0.05; **P < 0.001 (t‐test). (C–D) Young (2 months) and aged (12 months) male Ldlr−/− mice were placed on a HFD diet for the indicated time. At weekly intervals, peripheral blood was obtained and peripheral blood mononuclear cells were isolated. The cells were stained with fluorescently labeled monoclonal antibodies to assess patrolling monocytes CD115+, Ly6clo cells) (C) and inflammatory monocytes (CD115+, Ly6chi cells) (D). N = 15–20 mice group, error bars = SEM. Each data point per time interval was significantly different between the young and aged groups (P < 0.001, t‐test). (E) The aortas of Ldlr−/− young and aged mice maintained on a chow diet or given a HFD for 1 month were harvested, digested and their cellular suspensions were obtained. The cells were stained with fluorescently tagged monoclonal antibodies and fluorescent data acquired via flow cytometry. Macrophages defined as CD11b+, F4/80+GR1−. *P < 0.01 (t‐test). (F) As per E but mice were administered BrdU in the drinking water up to 1 week prior to tissue harvest.

Mentions: We next lethally irradiated aged and young Ldlr−/− mice and infused them i.v., with 1 × 107 bone marrow cells from either age‐matched or age‐mismatched Ldlr−/− bone marrow donors. Mice were left to rest for 2 months after bone marrow transplantation and then were fed a HFD for another 2 months after which time fasting plasma were obtained and cholesterol levels measured. Total cholesterol levels were similar among the chimeric groups (Fig. S5D). The mice were then euthanized and the degree of atherosclerosis was measured in the aortic root. We found that aged Ldlr−/− mice that received aged Ldlr−/− bone marrow exhibited larger atherosclerotic lesions than young mice that received young bone marrow (Fig. 5A–B), recapitulating the phenotype of nontransplanted aged and young mice (Fig. 1). Young mice that received aged bone marrow cells exhibited a significant 20–30% increase in lesion size compared to young mice that received young bone marrow cells, although this increase was still significantly smaller than that for aged mice that were infused with aged bone marrow (Fig. 5A). Aged mice that received young bone marrow exhibited a similar atherosclerotic lesion size as the aged‐to‐aged chimera (Fig. 5A). Thus, these data demonstrate that aged bone marrow cells contribute, but are not sufficient, to age‐enhanced atherosclerosis. Furthermore, the data also reveal that the presence of young bone marrow does not modulate the progression of atherosclerosis in aged hosts.


Age-associated vascular inflammation promotes monocytosis during atherogenesis.

Du W, Wong C, Song Y, Shen H, Mori D, Rotllan N, Price N, Dobrian AD, Meng H, Kleinstein SH, Fernandez-Hernando C, Goldstein DR - Aging Cell (2016)

Aging induces a peripheral monocytosis and increased macrophage numbers within the aorta. (A–B) Young (2 months of age) and aged (12 months of age) male Ldlr−/− mice were lethally irradiated and then reconstituted i.v. with 1 × 107 bone marrow cells from age‐matched or age‐mismatched Ldlr−/− donor mice. The mice were rested for 2 months and then fed a HFD for 2 months. Atherosclerotic lesion assessment was determined by lesion size in the aortic root by H&E. Blue scale bar = 100 μm. *P < 0.05; **P < 0.001 (t‐test). (C–D) Young (2 months) and aged (12 months) male Ldlr−/− mice were placed on a HFD diet for the indicated time. At weekly intervals, peripheral blood was obtained and peripheral blood mononuclear cells were isolated. The cells were stained with fluorescently labeled monoclonal antibodies to assess patrolling monocytes CD115+, Ly6clo cells) (C) and inflammatory monocytes (CD115+, Ly6chi cells) (D). N = 15–20 mice group, error bars = SEM. Each data point per time interval was significantly different between the young and aged groups (P < 0.001, t‐test). (E) The aortas of Ldlr−/− young and aged mice maintained on a chow diet or given a HFD for 1 month were harvested, digested and their cellular suspensions were obtained. The cells were stained with fluorescently tagged monoclonal antibodies and fluorescent data acquired via flow cytometry. Macrophages defined as CD11b+, F4/80+GR1−. *P < 0.01 (t‐test). (F) As per E but mice were administered BrdU in the drinking water up to 1 week prior to tissue harvest.
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acel12488-fig-0005: Aging induces a peripheral monocytosis and increased macrophage numbers within the aorta. (A–B) Young (2 months of age) and aged (12 months of age) male Ldlr−/− mice were lethally irradiated and then reconstituted i.v. with 1 × 107 bone marrow cells from age‐matched or age‐mismatched Ldlr−/− donor mice. The mice were rested for 2 months and then fed a HFD for 2 months. Atherosclerotic lesion assessment was determined by lesion size in the aortic root by H&E. Blue scale bar = 100 μm. *P < 0.05; **P < 0.001 (t‐test). (C–D) Young (2 months) and aged (12 months) male Ldlr−/− mice were placed on a HFD diet for the indicated time. At weekly intervals, peripheral blood was obtained and peripheral blood mononuclear cells were isolated. The cells were stained with fluorescently labeled monoclonal antibodies to assess patrolling monocytes CD115+, Ly6clo cells) (C) and inflammatory monocytes (CD115+, Ly6chi cells) (D). N = 15–20 mice group, error bars = SEM. Each data point per time interval was significantly different between the young and aged groups (P < 0.001, t‐test). (E) The aortas of Ldlr−/− young and aged mice maintained on a chow diet or given a HFD for 1 month were harvested, digested and their cellular suspensions were obtained. The cells were stained with fluorescently tagged monoclonal antibodies and fluorescent data acquired via flow cytometry. Macrophages defined as CD11b+, F4/80+GR1−. *P < 0.01 (t‐test). (F) As per E but mice were administered BrdU in the drinking water up to 1 week prior to tissue harvest.
Mentions: We next lethally irradiated aged and young Ldlr−/− mice and infused them i.v., with 1 × 107 bone marrow cells from either age‐matched or age‐mismatched Ldlr−/− bone marrow donors. Mice were left to rest for 2 months after bone marrow transplantation and then were fed a HFD for another 2 months after which time fasting plasma were obtained and cholesterol levels measured. Total cholesterol levels were similar among the chimeric groups (Fig. S5D). The mice were then euthanized and the degree of atherosclerosis was measured in the aortic root. We found that aged Ldlr−/− mice that received aged Ldlr−/− bone marrow exhibited larger atherosclerotic lesions than young mice that received young bone marrow (Fig. 5A–B), recapitulating the phenotype of nontransplanted aged and young mice (Fig. 1). Young mice that received aged bone marrow cells exhibited a significant 20–30% increase in lesion size compared to young mice that received young bone marrow cells, although this increase was still significantly smaller than that for aged mice that were infused with aged bone marrow (Fig. 5A). Aged mice that received young bone marrow exhibited a similar atherosclerotic lesion size as the aged‐to‐aged chimera (Fig. 5A). Thus, these data demonstrate that aged bone marrow cells contribute, but are not sufficient, to age‐enhanced atherosclerosis. Furthermore, the data also reveal that the presence of young bone marrow does not modulate the progression of atherosclerosis in aged hosts.

Bottom Line: In addition, in vitro cultures showed that aging enhanced the production of osteopontin by vascular smooth muscle cells.Functionally, aged atherosclerotic aortas displayed higher monocyte chemotaxis than young aortas.Hence, our study has revealed that aging induces metabolic dysfunction and enhances vascular inflammation to promote a peripheral monocytosis and macrophage accumulation within the atherosclerotic aorta.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

No MeSH data available.


Related in: MedlinePlus