Abstract

BackgroundMore 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.ResultsCardiac 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.ConclusionsOverall, these results suggested that targeting FGFR1 receptor signaling may represent a possible therapeutic strategy for preventing heart valve disease progression.

Highlights

  • 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

  • Fibroblast growth factor 1 (FGF1) and fibroblast growth factor 2 (FGF2) promoted cell proliferation in twodimensional valve interstitial cell culture FGF2 has been previously used in 2D valve interstitial cells (VIC) culture to maintain the cells in a quiescent, fibroblast-like state [11]

  • Immunofluorescence showed that cells in FGF1 and FGF2 media behaved in a different way compared to cells in 10% fetal bovine serum (FBS)-containing media (Fig. 2)

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Summary

Introduction

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. As the heart contracts and relaxes, its valves elegantly open and shut, maintaining unidirectional flow of blood. Throughout this dynamic process, resident valve cells actively remodel and maintain homeostasis via an intricate system of signaling networks between cells and their microenvironment. To prevent long-term damage to the heart, surgical intervention to replace heart valves is a must as currently there are no drug therapies to halt or reverse disease progression [2]. Researchers have sought to understand the cellular and molecular processes that underlie valve disease pathogenesis, hoping that it might possibly lead to nonsurgical treatment

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