Lysophosphatidylcholine activates the Akt pathway to upregulate extracellular matrix protein production in human aortic valve cells

Cheng, Hui; Yao, Qingzhou; Song, Rui; Zhai, Yufeng; Wang, Wei; Fullerton, David A.; Meng, Xianzhong

doi:10.1016/j.jss.2017.02.028

Cited by 16 publications

(11 citation statements)

References 35 publications

(42 reference statements)

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“…A number of studies have demonstrated that the Akt/mTOR signaling cascade is associated with cardiac hypertrophy [34, 35]. Akt is also involved in regulating the ability of oxidized low-density lipoprotein and lysophosphatydylcholine in the upregulation of ECM protein production in human aortic valve interstitial cells [36]. Accumulation of ECM proteins may contribute to the mechanism of valvular sclerosis associated with the development and progression of aortic stenosis [36].…”

Section: Discussionmentioning

confidence: 99%

“…Akt is also involved in regulating the ability of oxidized low-density lipoprotein and lysophosphatydylcholine in the upregulation of ECM protein production in human aortic valve interstitial cells [36]. Accumulation of ECM proteins may contribute to the mechanism of valvular sclerosis associated with the development and progression of aortic stenosis [36]. PI3K/Akt signaling was reported to modulate the NF-ĸB pathway and its downstream target IL-6 which in turn affected the calcification process of VICs [37].…”

Section: Discussionmentioning

confidence: 99%

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The role of fibroblast growth factor 1 and 2 on the pathological behavior of valve interstitial cells in a three-dimensional mechanically-conditioned model

2019

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Background More than five million Americans suffer from heart valve disease annually, a condition that worsens cardiac function and gradually leads to heart failure if appropriate treatment is not performed on time. Currently no medication can cure heart valve disease, leaving surgical intervention as the only viable option for patients at late stages of cardiac valve disease. Tremendous efforts have been undertaken to elucidate how resident cells in the valves respond to pathological stimulation as well as the underlying mechanisms that regulate these responses, to identify potential therapeutic targets for non-surgical treatment of valvular heart disease. Results Cardiac valve interstitial cells (VICs) naturally reside in a complex three-dimensional environment under varying hemodynamics, which is difficult to replicate in vitro . As a result, most cell signaling studies in the field have traditionally been conducted on two-dimensional models or in the absence of hemodynamic forces. Previously, we reported the fabrication of a hydrogel scaffold that could be used to culture valve cells under dynamic mechanical stimulation in a valve-mimetic environment. This model, therefore appeared to be suitable for VIC signaling studies as it provided cells a three-dimensional environment with the ability to incorporate mechanical stretching stimulation. Utilizing this model, we investigated the possible role of fibroblast growth factor 1 and 2 (FGF1 and FGF2) via FGFR1 receptor signaling in regulating valve cell activation under physiological (10% stretch) and pathological (20% stretch) mechanical conditions as well as in mediating cell proliferation and metabolism via the Akt/mTOR pathways. We reported that 1) FGF1 and FGF2 treatment was able to maintain the quiescent phenotype of VICs; 2) Cells increased proliferation as determined by optical redox ratios under elevated cyclic stretch via Akt/mTOR pathways; and 3) FGF1 and 2 signaling via the FGFR1 reduced VIC proliferation and activation under elevated cyclic stretch conditions. Conclusions Overall, these results suggested that targeting FGFR1 receptor signaling may represent a possible therapeutic strategy for preventing heart valve disease progression. Electronic supplementary material The online version of this article (10.1186/s13036-019-0168-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The role of fibroblast growth factor 1 and 2 on the pathological behavior of valve interstitial cells in a three-dimensional mechanically-conditioned model

2019

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“…LPC has been shown to stimulate Akt signaling pathway to up-regulate the production of extracellular matrix proteins such as biglycan, and type I collagen in human aortic valve cells [ 30 ]. But this effect of LPC is not mediated by MEK/ERK signaling [ 30 ]. These effects by LPC may contribute to valve sclerosis as well as aortic stenosis [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…But this effect of LPC is not mediated by MEK/ERK signaling [ 30 ]. These effects by LPC may contribute to valve sclerosis as well as aortic stenosis [ 30 ]. Limited information is known about the effect of LPC on PI3K/Akt signaling of endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidylcholine induces cytotoxicity/apoptosis and IL-8 production of human endothelial cells: Related mechanisms

et al. 2017

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Increased levels of oxidized low-density lipoprotein oxLDL) are shown to elevate the risk of cardiovascular diseases such as atherosclerosis, thrombosis, stroke, and myocardial infarction. This is possibly due to the toxic effects of oxLDLs on vascular cells. Various oxLDLs including lysophosphatidylcholine (LPC) and 7-ketocholesterol injure vascular endothelial cells and stimulate inflammatory reaction. However the toxicity of LPC on endothelial cells is not clear. In this study, human endothelial cells were exposed to LPC. Cytotoxicity was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Propidium iodide (PI) staining or PI/Annexin V dual staining flow cytometry were used to determine cell cycle progression and apoptosis. Reactive oxygen species (ROS) level was analyzed by DCFH-DA labeling flow cytometry. RNA and protein expression of endothelial cells was studied by reverse transcriptase-polymerase chain reaction and western blotting. IL-8 secretion was measured by enzyme-linked immunosorbant assay. LPC showed cytotoxicity to endothelial cells (>50 µg/ml). LPC induced cell cycle arrest and apoptosis with concomitant inhibition of cdc2 and cyclin B1 expression. LPC stimulated intracellular ROS production and ATM/Chk2, ATR/Chk1 and Akt activation. IL-8 expression and secretion in endothelial cells were induced by LPC. LPC-induced apoptosis, and IL-8 expression/secretion was attenuated by LY294002, a PI3K/Akt inhibitor. These results reveal that LPC is involved in the pathogenesis of atherosclerosis and vascular diseases by stimulation of inflammation and injury to endothelial cells. These events are related to ROS, ATM/Chk2, ATR/Chk2 and PI3K/Akt signaling. Understanding the toxic mechanisms of LPC is useful for future prevention and treatment atherosclerosis.

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“…It remains unknown from this study whether NT3 induces myofibroblastic transition in human AVICs to elevate their fibrogenic activity. Our previous studies found that soluble matrilin 2 upregulates α-smooth muscle action (α-SMA) levels and elevates the fibrogenic activity in human AVICs [35], while ox-LDL elevates human AVIC fibrogenic activity without the upregulation of cellular levels of α-SMA [36]. It appears that the induction of myofibroblastic transition in human AVICs is stimulus-specific and that either cell activation or cell phenotype transition may elevate human AVIC fibrogenic activity.…”

Section: Discussionmentioning

confidence: 99%

TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production

Yao

Zhai

et al. 2020

IJMS

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Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease that manifests as progressive valvular fibrosis and calcification. An inflammatory milieu in valvular tissue promotes fibrosis and calcification. Aortic valve interstitial cell (AVIC) proliferation and the over-production of the extracellular matrix (ECM) proteins contribute to valvular thickening. However, the mechanism underlying elevated AVIC fibrogenic activity remains unclear. Recently, we observed that AVICs from diseased aortic valves express higher levels of neurotrophin 3 (NT3) and that NT3 exerts pro-osteogenic and pro-fibrogenic effects on human AVICs. Hypothesis: Pro-inflammatory stimuli upregulate NT3 production in AVICs to promote fibrogenic activity in human aortic valves. Methods and Results: AVICs were isolated from normal human aortic valves and were treated with lipopolysaccharide (LPS, 0.20 µg/mL). LPS induced TLR4-dependent NT3 production. This effect of LPS was abolished by inhibition of the Akt and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways. The stimulation of TLR4 in human AVICs with LPS resulted in a greater proliferation rate and an upregulated production of matrix metallopeptidases-9 (MMP-9) and collagen III, as well as augmented collagen deposition. Recombinant NT3 promoted AVIC proliferation in a tropomyosin receptor kinase (Trk)-dependent fashion. The neutralization of NT3 or the inhibition of Trk suppressed LPS-induced AVIC fibrogenic activity. Conclusions: The stimulation of TLR4 in human AVICs upregulates NT3 expression and promotes cell proliferation and collagen deposition. The NT3-Trk cascade plays a critical role in the TLR4-mediated elevation of fibrogenic activity in human AVICs. Upregulated NT3 production by endogenous TLR4 activators may contribute to aortic valve fibrosis associated with CAVD progression.

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Lysophosphatidylcholine activates the Akt pathway to upregulate extracellular matrix protein production in human aortic valve cells

Cited by 16 publications

References 35 publications

The role of fibroblast growth factor 1 and 2 on the pathological behavior of valve interstitial cells in a three-dimensional mechanically-conditioned model

The role of fibroblast growth factor 1 and 2 on the pathological behavior of valve interstitial cells in a three-dimensional mechanically-conditioned model

Lysophosphatidylcholine induces cytotoxicity/apoptosis and IL-8 production of human endothelial cells: Related mechanisms

TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production

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