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The loss of CARMN regulates vascular smooth muscle cell phenotype and accelerates the development of atherosclerosis in mice.

ABSTRACT: The loss of CARMN regulates vascular smooth muscle cell phenotype and accelerates the development of atherosclerosis in mice.

PROVIDER: PRJNA667177 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12768337_1.fastq.gz	Fastqsanger.gz
	SRR12768337_2.fastq.gz	Fastqsanger.gz
	SRR12768338_1.fastq.gz	Fastqsanger.gz
	SRR12768338_2.fastq.gz	Fastqsanger.gz
	SRR12768339_1.fastq.gz	Fastqsanger.gz

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Project description:Background Vascular calcification contributes to cardiovascular disease. One important process is the phenotypic transition of vascular smooth muscle cells (SMCs) from a contractile to a mineralizing phenotype, releasing calcifying extracellular vesicles (EVs). The endolysosomal system is involved in EV biogenesis and regulates essential cell physiological functions. We hypothesize that alterations in endomembrane homeostasis affect SMC phenotypic identity and EV cargo, thereby regulating vascular calcification. Results In human calcified carotid plaques and calcifying SMCs, the abundance of FYVE-Type Zinc Finger Containing Phosphoinositide Kinase (PIKfyve), an essential lipid kinase, in the endomembrane maturation, is increased. Phosphatidylinositol 3-phosphate (PI3P) - the substrate of PIKfyve - was decreased in cellular membranes of calcifying SMCs (-40%) and recovered by Apilimod, a small molecule PIKfyve inhibitor. In vitro, Apilimod reduced the osteogenic features, like matrix mineralization (-77%), collagen secretion (-99%), and tissue non-specific alkaline phosphatase (TNAP) protein expression (-86%) in calcifying SMCs. Moreover, Apilimod-induced EVs exhibited fewer mineral-positive EVs and reduced aggregation potential (-80%), suggesting diminished EV calcification potential. A proteomic analysis of the EV cargo demonstrated that Apilimod reduces TNAP cargo, which was supported by western blot. In a murine atherosclerosis model, Apilimod reduced aortic calcification assessed by ex vivo osteosense imaging. Transcriptomics revealed phenotypic transitions of calcifying SMCs after PIKfyve inhibition. Apilimod promoted adipogenic markers (PPARG: +218%, FABP3: +2250%), fatty acid uptake (+86%), lipid droplets (OilRed, Raman spectroscopy), and increased the expression of macrophage-like SMC markers (CD68: +500%; LGALS3: +132%), suggesting an alternative SMC phenotype. Kinome and in silico analyses identified YAP1 deactivation as a potential mechanism. Re-activation of YAP1 partially antagonized Apilimod-dependent effects in calcifying SMCs. Conclusion PIKfyve inhibition inhibits the osteogenic transition of SMCs while promoting a phenotypic adaptation towards adipogenic/pro-inflammatory SMCs, which is partially mediated by YAP1. The phenotypic identity of calcifying SMCs is sensitive to alterations of the endomembrane homeostasis.

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The loss of CARMN regulates vascular smooth muscle cell phenotype and accelerates the development of atherosclerosis in mice.

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