Abstract
In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics.
Original language | English |
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Article number | e0146415 |
Journal | PLoS ONE |
Volume | 11 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2016 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2016 Horton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding
This work was funded by the National Institutes of Health (www.nih.gov) Grants 1 UH2 TR000522-01, 4 UH3TR000522-03, the Harvard Materials Research Science and Engineering Center (MRSEC) as supported by National Science Foundation (www.nsf.gov) Division of Materials Research Grant DMR-1420570, and the Harvard School of Engineering and Applied Sciences. The funding institutions had no role in the study design, data collection and analysis, manuscript preparation, or the decision to publish. TR000522-01, 4 UH3TR000522-03, the Harvard Materials Research Science and Engineering Center (MRSEC) as supported by National Science Foundation (www.nsf.gov) Division of Materials Research Grant DMR-1420570, and the Harvard School of Engineering and Applied Sciences. The funding institutions had no role in the study design, data collection and analysis, manuscript preparation, or the decision to publish. Funding: This work was funded by the National Institutes of Health (www.nih.gov) Grants 1 UH2
Funders | Funder number |
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National Science Foundation | DMR-1420570 |
National Institutes of Health | 1 UH2 |
National Center for Advancing Translational Sciences | UH3TR000522 |
Harvard School of Engineering and Applied Sciences | |
Materials Research Science and Engineering Center, Harvard University |