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AMP-Activated Protein Kinase ?1 in Macrophages Promotes Collateral Remodeling and Arteriogenesis in Mice In Vivo.

ABSTRACT: OBJECTIVE:AMP-activated protein kinase (AMPK), an energy and redox sensor, is activated in response to various cellular stresses, including hypoxia, nutrient deprivation, oxidative stress, and fluid shear stress at the site of vessel blockade. The activation of AMPK is involved in angiogenesis. However, it is unknown whether AMPK can influence arteriogenesis. Here, we demonstrate the contribution of macrophage AMPK to arteriogenesis and collateral remodeling and their underlying mechanisms in well-characterized in vivo and in vitro models. APPROACH AND RESULTS:AMPK?1, AMPK?2 knockout and wild-type littermates underwent femoral artery ligation. Collateral arteriogenesis was monitored in wild-type, global AMPK?1 knockout, or macrophage-specific AMPK?1 knockout mice, with or without hindlimb ligation. Compared with wild-type mice with ligation, global AMPK?1 knockout mice displayed significant reduction in blood flow recovery and impaired remodeling of collateral arterioles. Similar impairments were observed in macrophage-specific AMPK ?1 knockout mice after hindlimb ligation. Mechanistically, we found that AMPK?1 promotes the production of growth factors, such as transforming growth factor ?, by directly phosphorylating the inhibitor of nuclear factor ?B kinase alpha, resulting in an nuclear factor ?B-dependent production of growth factors CONCLUSIONS:Our findings suggest a novel role for macrophage AMPK?1 in arteriogenesis and collateral remodeling and indicate that AMPK?1 activation might be beneficial for recovery from occlusive vascular disorders.

SUBMITTER: Zhu H

PROVIDER: S-EPMC6408938 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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AMP-Activated Protein Kinase α1 in Macrophages Promotes Collateral Remodeling and Arteriogenesis in Mice In Vivo.

Zhu Huaiping H Zhang Miao M Liu Zhaoyu Z Xing Junjie J Moriasi Cate C Dai Xiaoyan X Zou Ming-Hui MH

Arteriosclerosis, thrombosis, and vascular biology 20160721 9

<h4>Objective</h4>AMP-activated protein kinase (AMPK), an energy and redox sensor, is activated in response to various cellular stresses, including hypoxia, nutrient deprivation, oxidative stress, and fluid shear stress at the site of vessel blockade. The activation of AMPK is involved in angiogenesis. However, it is unknown whether AMPK can influence arteriogenesis. Here, we demonstrate the contribution of macrophage AMPK to arteriogenesis and collateral remodeling and their underlying mechanis ...[more]

PMID: 27444205

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Project description:BackgroundAMP-activated protein kinase (Ampk) is a sensor of the cellular energy status and a powerful regulator of metabolism. Activation of Ampk was previously shown to participate in monocyte-to-fibroblast transition and matrix protein production in renal tissue. Thus, the present study explored whether the catalytic Ampkα1 isoform participates in the regulation of the renal fibrotic response following unilateral ureteral obstruction (UUO).MethodsUUO was induced in gene-targeted mice lacking functional Ampkα1 (Ampkα1-/-) and in corresponding wild-type mice (Ampkα1+/+). In the obstructed kidney and, for comparison, in the non-obstructed control kidney, quantitative RT-PCR, Western blotting and immunostaining were employed to determine transcript levels and protein abundance, respectively.ResultsIn Ampkα1+/+ mice, UUO significantly up-regulated the protein abundance of the Ampkα1 isoform, but significantly down-regulated the Ampkα2 isoform in renal tissue. Phosphorylated Ampkα protein levels were significantly increased in obstructed kidney tissue of Ampkα1+/+ mice but not of Ampkα1-/- mice. Renal expression of α-smooth muscle actin was increased following UUO, an effect again less pronounced in Ampkα1-/- mice than in Ampkα1+/+ mice. Histological analysis did not reveal a profound effect of Ampkα1 deficiency on collagen 1 protein deposition. UUO significantly increased phosphorylated and total Tgf-ß-activated kinase 1 (Tak1) protein, as well as transcript levels of Tak1-downstream targets c-Fos, Il6, Pai1 and Snai1 in Ampkα1+/+ mice, effects again significantly ameliorated in Ampkα1-/- mice. Moreover, Ampkα1 deficiency inhibited the UUO-induced mRNA expression of Cd206, a marker of M2 macrophages and of Cxcl16, a pro-fibrotic chemokine associated with myeloid fibroblast formation. The effects of Ampkα1 deficiency during UUO were, however, paralleled by increased tubular injury and apoptosis.ConclusionsRenal obstruction induces an isoform shift from Ampkα2 towards Ampkα1, which contributes to the signaling involved in cell survival and fibrosis.

Dataset Information

AMP-Activated Protein Kinase ?1 in Macrophages Promotes Collateral Remodeling and Arteriogenesis in Mice In Vivo.

Publications

AMP-Activated Protein Kinase α1 in Macrophages Promotes Collateral Remodeling and Arteriogenesis in Mice In Vivo.

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