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Gender Dependent Role of Akt3 in Ath...

Zhang, Lifang,

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Gender Dependent Role of Akt3 in Atherosclerosis /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Gender Dependent Role of Akt3 in Atherosclerosis // Lifang Zhang.
作者:	Zhang, Lifang,
面頁冊數:	1 electronic resource (121 pages)
附註:	Source: Dissertations Abstracts International, Volume: 87-01, Section: B.
Contained By:	Dissertations Abstracts International87-01B.
標題:	Immunology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=32184381
ISBN:	9798286450626

Gender Dependent Role of Akt3 in Atherosclerosis /
Zhang, Lifang,

Gender Dependent Role of Akt3 in Atherosclerosis /Lifang Zhang. - 1 electronic resource (121 pages)

Source: Dissertations Abstracts International, Volume: 87-01, Section: B.

Akt3, along with Akt1 and Akt2, is one of the three members of the Akt family, also known as serine/threonine kinase Akt/protein kinase B family. The Akt kinase pathway plays a crucial role in regulating multiple cellular processes by phosphorylating downstream substrates in response to the binding of ligand to a cell membrane receptor. This includes cell survival, cell growth, cell differentiation, cell migration, cell apoptosis, as well as glucose and lipid metabolism. Previous studies in our lab have demonstrated that global knockout of Akt3 in mice promotes atherogenesis in a macrophage-dependent manner.In this study, we focus on investigating whether enhanced Akt3 kinase activity in mice reduces atherosclerosis, and whether this effect is gender dependent, in addition to identifying the potential mechanism. We crossed atherosclerosis prone ApoE knockout (ApoE-/-) mice with a mouse strain, Akt3nmf350, which has a missense mutation in the Akt3 gene that results in enhanced Akt3 kinase activity. We then assessed atherosclerotic lesion formation after 15 weeks of high fat diet feeding and investigated the role of macrophages in atherogenesis. Significant reduction of atherosclerotic lesion area and in macrophage accumulation in lesions were observed in ApoE-/-/Akt3nmf350 mice fed high fat diet, compared to ApoE-/- mice.Furthermore, experiments using chimeric ApoE-/- mice with either ApoE-/- bone marrow or ApoE-/-/Akt3nmf350 bone marrow cells showed that enhanced Akt3 kinase activity is atheroprotective, presumably through bone-marrow-derived macrophages.Atherosclerotic lesion analysis demonstrated that the atheroprotective effect of enhanced Akt3 activity was more pronounced in male mice. In line with this result, release of the pro-inflammatory cytokines IL-6, TNF-α, MCP-1, and MIP-1? was reduced by macrophages collected from male but not female ApoE-/-/Akt3nmf350 mice. Levels of IL-6 and TNF-α were also reduced in atherosclerotic lesions of ApoE-/-/Akt3nmf350 male mice compared to ApoE-/- mice. Macrophages from male ApoE-/-/Akt3nmf350 mice were also more resistant to apoptosis in vitro and in vivo and tended to have higher migration capability and more pronounced M2 polarization in vitro.These findings suggested that enhanced Akt3 kinase activity may protect hyperlipidemic mice from the development of atherosclerosis by regulating macrophage function in a gender dependent manner.

English

ISBN: 9798286450626Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Atherosclerosis

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520 $a Akt3, along with Akt1 and Akt2, is one of the three members of the Akt family, also known as serine/threonine kinase Akt/protein kinase B family. The Akt kinase pathway plays a crucial role in regulating multiple cellular processes by phosphorylating downstream substrates in response to the binding of ligand to a cell membrane receptor. This includes cell survival, cell growth, cell differentiation, cell migration, cell apoptosis, as well as glucose and lipid metabolism. Previous studies in our lab have demonstrated that global knockout of Akt3 in mice promotes atherogenesis in a macrophage-dependent manner.In this study, we focus on investigating whether enhanced Akt3 kinase activity in mice reduces atherosclerosis, and whether this effect is gender dependent, in addition to identifying the potential mechanism. We crossed atherosclerosis prone ApoE knockout (ApoE-/-) mice with a mouse strain, Akt3nmf350, which has a missense mutation in the Akt3 gene that results in enhanced Akt3 kinase activity. We then assessed atherosclerotic lesion formation after 15 weeks of high fat diet feeding and investigated the role of macrophages in atherogenesis. Significant reduction of atherosclerotic lesion area and in macrophage accumulation in lesions were observed in ApoE-/-/Akt3nmf350 mice fed high fat diet, compared to ApoE-/- mice.Furthermore, experiments using chimeric ApoE-/- mice with either ApoE-/- bone marrow or ApoE-/-/Akt3nmf350 bone marrow cells showed that enhanced Akt3 kinase activity is atheroprotective, presumably through bone-marrow-derived macrophages.Atherosclerotic lesion analysis demonstrated that the atheroprotective effect of enhanced Akt3 activity was more pronounced in male mice. In line with this result, release of the pro-inflammatory cytokines IL-6, TNF-α, MCP-1, and MIP-1? was reduced by macrophages collected from male but not female ApoE-/-/Akt3nmf350 mice. Levels of IL-6 and TNF-α were also reduced in atherosclerotic lesions of ApoE-/-/Akt3nmf350 male mice compared to ApoE-/- mice. Macrophages from male ApoE-/-/Akt3nmf350 mice were also more resistant to apoptosis in vitro and in vivo and tended to have higher migration capability and more pronounced M2 polarization in vitro.These findings suggested that enhanced Akt3 kinase activity may protect hyperlipidemic mice from the development of atherosclerosis by regulating macrophage function in a gender dependent manner.
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