Inflammation Drives Retraction, Stiffening, and Nodule Formation via Cytoskeletal Machinery in a Three-Dimensional Culture Model of Aortic Stenosis

Lim, Jina; Ehsanipour, Arshia; Hsu, Jeffrey J.; Lu, Jianqin; Pedego, Taylor M.; Wu, Alexander; Walthers, Chris M.; Demer, Linda L.; Seidlits, Stephanie K.; Tintut, Yin

doi:10.1016/j.ajpath.2016.05.003

Cited by 26 publications

(20 citation statements)

References 47 publications

(38 reference statements)

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“…Aortic valve leaflets were carefully excised from C57BL/6 mice and cultured via an explant technique, as described previously. 27 Cells were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 20% fetal bovine serum (FBS), penicillin, and streptomycin. For osteoblastic differentiation, cells were cultured in alphaminimum essential medium supplemented with 10% FBS (charcoal stripped FBS), 5 mmol/L beta-glycerophosphate and 50 μg/ml of ascorbic acid, and indicated agents.…”

Section: Vic Isolation and Characterizationmentioning

confidence: 99%

“…We next tested the effects on inflammationinduced matrix mineralization of VICs, using the proinflammatory cytokine, TNF-α, which we found to induce matrix mineralization of VIC. 27 VICs were treated with 5-HT and/or TNF-α, and matrix calcification was assessed qualitatively by alizarin red staining and quantitatively by o-cresolphthalein complexone. Results showed that TNF-α-induced matrix mineralization of VIC was augmented by 5-HT ( Figure 2B).…”

Section: Effects Of 5-ht On Tnf-α Induction Of Matrix Mineralizatiomentioning

confidence: 99%

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

Fong

Xian

Demer

et al. 2020

J of Cellular Biochemistry

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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 inflammationinduced matrix mineralization in valve cells. Real-time reverse transcriptionpolymerase 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-αinduced 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.

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Section: Vic Isolation and Characterizationmentioning

confidence: 99%

Section: Effects Of 5-ht On Tnf-α Induction Of Matrix Mineralizatiomentioning

confidence: 99%

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

Fong

Xian

Demer

et al. 2020

J of Cellular Biochemistry

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“…Previously considered a degenerative process, cardiovascular calcification is now established as a regulated process ( 1 – 3 ) in which vascular and valvular mesenchymal cells undergo osteogenic differentiation ( 4 – 8 ). Clinically, vascular calcification is considered pathognomonic of atherosclerosis.…”

Section: Significance Of Cardiovascular Calcificationmentioning

confidence: 99%

Lipoproteins in Cardiovascular Calcification: Potential Targets and Challenges

Tintut

Hsu

Demer

2018

Front. Cardiovasc. Med.

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Previously considered a degenerative process, cardiovascular calcification is now established as an active process that is regulated in several ways by lipids, phospholipids, and lipoproteins. These compounds serve many of the same functions in vascular and valvular calcification as they do in skeletal bone calcification. Hyperlipidemia leads to accumulation of lipoproteins in the subendothelial space of cardiovascular tissues, which leads to formation of mildly oxidized phospholipids, which are known bioactive factors in vascular cell calcification. One lipoprotein of particular interest is Lp(a), which showed genome-wide significance for the presence of aortic valve calcification and stenosis. It carries an important enzyme, autotaxin, which produces lysophosphatidic acid (LPA), and thus has a key role in inflammation among other functions. Matrix vesicles, extruded from the plasma membrane of cells, are the sites of initiation of mineral formation. Phosphatidylserine, a phospholipid in the membranes of matrix vesicles, is believed to complex with calcium and phosphate ions, creating a nidus for hydroxyapatite crystal formation in cardiovascular as well as in skeletal bone mineralization. This review focuses on the contributions of lipids, phospholipids, lipoproteins, and autotaxin in cardiovascular calcification, and discusses possible therapeutic targets.

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“…39 69 70 Since unopposed positive feedback loops are unstable, some form of negative feedback must also arise, such as the induction of inhibitors like MGP.…”

Section: Positive Feedbackmentioning

confidence: 99%

Cell-matrix mechanics and pattern formation in inflammatory cardiovascular calcification

Hsu

Lim

Tintut

et al. 2016

Heart

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Calcific diseases of the cardiovascular system, such as atherosclerotic calcification and calcific aortic valve disease, are widespread and clinically significant, causing substantial morbidity and mortality. Vascular cells, like bone cells, interact with their matrix substrate not only through molecular signals, but also through biomechanical signals, such as traction forces transmitted from cytoskeleton to matrix. The interaction of contractile vascular cells with their matrix may be one of the most important factors controlling pathological mineralization of the artery wall and cardiac valves. In many respects, the matricrine and matrix mechanical changes in calcific vasculopathy and valvulopathy resemble those occurring in embryonic bone development and normal bone mineralization. The matrix proteins provide not only a microenvironment for propagation of crystal growth but also provide mechanical cues to the cells that direct differentiation. Small contractions of the cytoskeleton may tug on integrin links to sites on matrix proteins, and thereby sense the stiffness, possibly through deformation of binding proteins causing release of differentiation factors such as products of the members of the transforming growth factor-beta superfamily. Inflammation and matrix characteristics are intertwined: inflammation alters the matrix such as through matrix metalloproteinases, while matrix mechanical properties affect cellular sensitivity to inflammatory cytokines. The adhesive properties of matrix also regulate self-organization of vascular cells into patterns through reaction-diffusion phenomena and left-right chirality. In this review, we summarize the roles of extracellular matrix proteins and biomechanics in the development of inflammatory cardiovascular calcification.

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Inflammation Drives Retraction, Stiffening, and Nodule Formation via Cytoskeletal Machinery in a Three-Dimensional Culture Model of Aortic Stenosis

Cited by 26 publications

References 47 publications

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

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

Lipoproteins in Cardiovascular Calcification: Potential Targets and Challenges

Cell-matrix mechanics and pattern formation in inflammatory cardiovascular calcification

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