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SNRK (Sucrose Nonfermenting 1-Related Kinase) Promotes Angiogenesis In Vivo. Arterioscler Thromb Vasc Biol 2018 02;38(2):373-385

Date

12/16/2017

Pubmed ID

29242271

Pubmed Central ID

PMC5785416

DOI

10.1161/ATVBAHA.117.309834

Abstract

OBJECTIVE: SNRK (sucrose nonfermenting 1-related kinase) is a novel member of the AMPK (adenosine monophosphate-activated protein kinase)-related superfamily that is activated in the process of angiogenesis. Currently, little is known about the function of SNRK in angiogenesis in the physiological and pathological conditions.

APPROACH AND RESULTS: In this study, in Snrk global heterozygous knockout mice, retina angiogenesis and neovessel formation after hindlimb ischemia were suppressed. Consistently, mice with endothelial cell (EC)-specific Snrk deletion exhibited impaired retina angiogenesis, and delayed perfusion recovery and exacerbated muscle apoptosis in ischemic hindlimbs, compared with those of littermate wide-type mice. Endothelial SNRK expression was increased in the extremity vessel samples from nonischemic human. In ECs cultured in hypoxic conditions, HIF1α (hypoxia inducible factor 1α) bound to the SNRK promoter to upregulate SNRK expression. In the nuclei of hypoxic ECs, SNRK complexed with SP1 (specificity protein 1), and together, they bound to an SP1-binding motif in the ITGB1 (β1 integrin) promoter, resulting in enhanced ITGB1 expression and promoted EC migration. Furthermore, SNRK or SP1 deficiency in ECs ameliorated hypoxia-induced ITGB1 expression and, consequently, inhibited EC migration and angiogenesis.

CONCLUSIONS: Taken together, our data have revealed that SNRK/SP1-ITGB1 signaling axis promotes angiogenesis in vivo.

Author List

Lu Q, Xie Z, Yan C, Ding Y, Ma Z, Wu S, Qiu Y, Cossette SM, Bordas M, Ramchandran R, Zou MH

Author

Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antigens, CD
Apoptosis
Blood Flow Velocity
Cadherins
Cell Movement
Cell Proliferation
Cells, Cultured
Disease Models, Animal
Endothelial Cells
Gene Expression Regulation, Enzymologic
Hindlimb
Human Umbilical Vein Endothelial Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Integrin beta1
Ischemia
Lung
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal
Neovascularization, Physiologic
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases
Regional Blood Flow
Retinal Vessels
Sp1 Transcription Factor
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d