Lipoprotein(a) Induces Vesicular Cardiovascular Calcification Revealed With Single-Extracellular Vesicle Analysis.

Autor:	Rogers MA; Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States., Atkins SK; Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States., Zheng KH; Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States.; Department of Vascular Medicine, Academic Medical Center, Amsterdam UMC, Amsterdam, Netherlands., Singh SA; Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States., Chelvanambi S; Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States., Pham TH; Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States., Kuraoka S; Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States., Stroes ESG; Department of Vascular Medicine, Academic Medical Center, Amsterdam UMC, Amsterdam, Netherlands., Aikawa M; Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States.; Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States., Aikawa E; Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States.; Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2022 Jan 28; Vol. 9, pp. 778919. Date of Electronic Publication: 2022 Jan 28 (Print Publication: 2022).
DOI:	10.3389/fcvm.2022.778919
Abstrakt:	Lipoprotein(a) (Lp[a]) blood levels >50 mg/dL is a major cardiovascular disease risk factor in humans. Lp(a) associates with increased cardiovascular calcification, a critical pathology with no clinically available drug therapies. The mechanisms through which Lp(a) increases cardiovascular calcification risk remain undefined. We hypothesized that Lp(a) promotes the release of calcifying extracellular vesicles (EVs) that contribute to formation of microcalcification in cardiovascular tissues. Here, we show Lp(a) increased calcification in both primary human smooth muscle cells (SMCs) and valvular interstitial cells (VICs), potentially through inflammation-related mechanisms that were suppressed with E06 antibody that neutralizes pro-inflammatory oxidized phospholipids. Incubating human SMCs and VICs with Lp(a) altered the composition of EVs, increasing CD29 + /tetraspanin - microvesicle release, demonstrated with a tailored single-EV microarray assay that can distinguish multivesicular body-derived exosomes and plasma membrane budded microvesicles at a single-vesicle level. Lp(a) stimulation led to release of SMC and VIC EVs that readily calcified in acellular 3D-collagen hydrogels mimicking formation of ectopic microcalcification occurring in extracellular matrix of human atherosclerotic arteries and stenotic aortic valves. Our study mechanistically demonstrates that Lp(a) partially mediates cardiovascular calcification formation via inducing the release of calcifying EVs. Additionally, we provide a customized method to assess calcifying EVs at a single-vesicle level that can be more broadly applied to assist in quantitatively differentiating exosome and microvesicle EV subpopulations. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Rogers, Atkins, Zheng, Singh, Chelvanambi, Pham, Kuraoka, Stroes, Aikawa and Aikawa.)
Databáze:	MEDLINE
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