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Local Renin-Angiotensin System Signaling Mediates Cellular Function of Aortic Valves

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Abstract

The renin-angiotensin system (RAS) is activated in aortic valve disease, yet little is understood about how it affects the acute functional response of valve interstitial cells (VICs). Herein, we developed a gelatin-based valve thin film (vTF) platform to investigate whether the contractile response of VICs can be regulated via RAS mediators and inhibitors. First, the impact of culture medium (quiescent, activated, and osteogenic medium) on VIC phenotype and function was assessed. Contractility of VICs was measured upon treatment with angiotensin I (Ang I), angiotensin II (Ang II), angiotensin-converting enzyme (ACE) inhibitor, and Angiotensin II type 1 receptor (AT1R) inhibitor. Anisotropic cell alignment on gelatin vTF was achieved independent of culture conditions. Cells cultured in activated and osteogenic conditions were found to be more elongated than in quiescent medium. Increased α-SMA expression was observed in activated medium and no RUNX2 expression were observed in cells. VIC contractile stress increased with increasing concentrations (from 10−10 to 10−6 M) of Ang I and Ang II. Moreover, cell contraction was significantly reduced in all ACE and AT1R inhibitor-treated groups. Together, these findings suggest that local RAS is active in VICs, and our vTF may provide a powerful platform for valve drug screening and development.

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Abbreviations

ACE:

Angiotensin-converting enzyme

Ang I:

Angiotensin I

Ang II:

Angiotensin II

AT1R:

Angiotensin II type 1 receptor

AT2R:

Angiotensin II type 2 receptor

mTG:

Microbial transglutaminase

RAS:

Renin-angiotensin system

VIC:

Valve interstitial cells

vTF:

Valve thin film

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Funding

This research was supported by the American Heart Association under Grant Numbers 18AIREA33900098 (K.B.) and 19PRE34370061 (I.T.) and the Arkansas Biosciences Institute (K.B.).

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All authors declare that they have no conflicts of interest or financial ties to disclose.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Arkansas, 122 John A.White Jr. Engineering Hall, Fayetteville, AR, 72701, USA

    Asya Ozkizilcik, Fah Sysavanh, Smit Patel, Ishita Tandon & Kartik Balachandran

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  1. Asya Ozkizilcik
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  2. Fah Sysavanh
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  3. Smit Patel
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Correspondence to Kartik Balachandran.

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Ozkizilcik, A., Sysavanh, F., Patel, S. et al. Local Renin-Angiotensin System Signaling Mediates Cellular Function of Aortic Valves. Ann Biomed Eng 49, 3550–3562 (2021). https://doi.org/10.1007/s10439-021-02876-y

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