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Serotonin receptor type 2B activation augments TNF-α-induced matrix mineralization in murine valvular interstitial cells.

ABSTRACT: Calcification, fibrosis, and chronic inflammation are the predominant features of calcific aortic valve disease, a life-threatening condition. Drugs that induce serotonin (5-hydroxytryptamine [5-HT]) are known to damage valves, and activated platelets, which carry peripheral serotonin, are known to promote calcific aortic valve stenosis. However, the role of 5-HT in valve leaflet pathology is not known. We tested whether serotonin mediates inflammation-induced matrix mineralization in valve cells. Real-time reverse transcription-polymerase chain reaction analysis showed that murine aortic valve interstitial cells (VICs) expressed both serotonin receptor types 2A and 2B (Htr2a and Htr2b). Although Htr2a expression was greater at baseline, Htr2b expression was induced several-fold more than Htr2a in response to the pro-calcific tumor necrosis factor-α (TNF-α) treatment. 5-HT also augmented TNF-α-induced osteoblastic differentiation and matrix mineralization of VIC, but 5-HT alone had no effects. Inhibition of serotonin receptor type 2B, using specific inhibitors or lentiviral knockdown in VIC, attenuated 5-HT effects on TNF-α-induced osteoblastic differentiation and mineralization. 5-HT treatment also augmented TNF-α-induced matrix metalloproteinase-3 expression, which was also attenuated by Htr2b knockdown. Htr2b expression in aortic roots and serum levels of peripheral 5-HT were also greater in the hyperlipidemic Apoe^-/- mice than in control normolipemic mice. These findings suggest a new role for serotonin signaling in inflammation-induced calcific valvulopathy.

SUBMITTER: Fong F

PROVIDER: S-EPMC7770058 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Collagen networks within 3D PEG hydrogels support valvular interstitial cell matrix mineralization.

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| S-EPMC7738375 | biostudies-literature

Sam68 promotes osteogenic differentiation of aortic valvular interstitial cells by TNF-α/STAT3/autophagy axis.

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| S-EPMC10409708 | biostudies-literature

Comparison of Serotonin-Regulated Calcific Processes in Aortic and Mitral Valvular Interstitial Cells.

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| S-EPMC8340088 | biostudies-literature

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| S-EPMC4040249 | biostudies-literature

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| S-EPMC2819994 | biostudies-literature

Rapamycin Augments the NMDA-Mediated TNF Suppression of MRSA-Stimulated RAW264.7 Murine Macrophages.

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| S-EPMC3474976 | biostudies-literature

Myofibroblastic activation of valvular interstitial cells is modulated by spatial variations in matrix elasticity and its organization.

Project description:Valvular interstitial cells (VICs) are key regulators of the heart valve's extracellular matrix (ECM), and upon tissue damage, quiescent VIC fibroblasts become activated to myofibroblasts. As the behavior of VICs during disease progression and wound healing is different compared to healthy tissue, we hypothesized that the organization of the matrix mechanics, which results from depositing of collagen fibers, would affect VIC phenotypic transition. Specifically, we investigated how the subcellular organization of ECM mechanical properties affects subcellular localization of Yes-associated protein (YAP), an early marker of mechanotransduction, and α-smooth muscle actin (α-SMA), a myofibroblast marker, in VICs. Photo-tunable hydrogels were used to generate substrates with different moduli and to create organized and disorganized patterns of varying elastic moduli. When porcine VICs were cultured on these matrices, YAP and α-SMA activation were significantly increased on substrates with higher elastic modulus or a higher percentage of stiff regions. Moreover, VICs cultured on substrates with a spatially disorganized elasticity had smaller focal adhesions, less nuclear localized YAP, less α-SMA organization into stress fibers and higher proliferation compared to those cultured on substrates with a regular mechanical organization. Collectively, these results suggest that disorganized spatial variations in mechanics that appear during wound healing and fibrotic disease progression may influence the maintenance of the VIC fibroblast phenotype, causing more proliferation, ECM remodeling and matrix deposition.

| S-EPMC5452973 | biostudies-literature

Statins block calcific nodule formation of valvular interstitial cells by inhibiting alpha-smooth muscle actin expression.

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| S-EPMC2766347 | biostudies-literature

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