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The Role of Tissue Modulus and Cardiac Fibroblast Phenotype in Volume Overload Induced Heart Failure

Childers, Rachel Caitlin
http://orcid.org/0000-0001-9430-4897
http://rave.ohiolink.edu/etdc/view?acc_num=osu1480335744116284

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biomedical Engineering.
Volume overload (VO) induced heart failure results from an increase in blood volume (preload) to the heart. The heart responds to increases in hemodynamic load through compensative remodeling. VO has a distinct pattern of remodeling compared to pressure overload induced heart failure, which results in fibrosis. VO results in a net decrease in extracellular matrix (ECM). This loss of ECM contributes to the progression of the disease due to the loss of structural integrity. Since cardiac fibroblasts (CFs) are the main cells responsible for maintaining ECM in the heart, we characterized the in vitro phenotype of CFs isolated from a rat VO model, aortocaval fistula (ACF). Compared to sham operated animals, ACF fibroblasts displayed a phenotype that we described as “hypofibrotic”. ACF CFs secreted relatively less collagen and profibrotic molecules, such as a-smooth muscle actin (aSMA) and connective tissue growth factor (CTGF). Interestingly, ACFs produce approximately twice as much transforming growth factor-ß1 (TGF-ß), a key profibrotic stimulus, as their sham counterparts. However, there were no changes in the canonical TGF-ß pathway that could account for the hypofibrotic phenotype observed in ACF fibroblasts. Since others have shown that the cytoskeleton and the Rho/ROCK pathway play a role in fibroblast phenotype, we characterized the actin cytoskeleton in sham and ACF fibroblasts. We found that ACF CFs have significantly less F-actin than sham CFs. We were able to show that it is possible the actin cytoskeleton might account for phenotypic differences in CFs by chemically altering the amounts of F-actin and G-actin. When the cells were treated with a ROCK inhibitor, which allows F-actin to depolymerize into G-actin, CFs displayed a more hypofibrotic phenotype. Conversely, enhancement of F-actin with jasplakinolide treatment forced the CFs to have a profibrotic phenotype. Numerous studies have linked substrate modulus with effects on the cytoskeleton. Stiff substrates tend to increase cytoskeletal organization and increase F-actin resulting in stress fiber formation in vitro. We wondered if changes in tissue modulus may account for differences in observed phenotype. To know if changes in tissue modulus account for changes in CF phenotype, we first characterized the tissue stiffness changes. We used biaxial tensile testing, which yields a direct measure of tissue modulus, an intrinsic property of the material. Here we show that ACF rats have approximately half the tissue modulus compared to control rats. Since increased stiffness is positively correlated with CF changes towards a more profibrotic phenotype, we postulated that decreased substrate stiffness may lead to a more hypofibrotic phenotype. Specifically, we hypothesized that sham CFs on softer substrates would have a more hypo-fibrotic phenotype; conversely, CFs from ACF would behave more like normal cells on a higher stiffness. Although the phenotype of sham CFs was shifted to a more hypofibrotic direction on soft substrates, ACF fibroblasts had many indications of a dampened response to stiffness reminiscent of the effect known as “mechanical memory” described by others 1,2.
Keith Gooch, PhD (Advisor)
Jun Liu, PhD (Committee Member)
Pamela Lucchesi, PhD (Committee Member)
Aaron Trask, PhD (Committee Member)
128 p.
Biomedical Engineering
heart failure; volume overload; remodeling; modulus; cardiac fibroblast; phenotype; stiffness; fibrosis; pressure overload; ECM; biaxial testing; PV loops; TGF-beta; cytoskeleton

Recommended Citations

Citations

  • Childers, R. C. (2016). The Role of Tissue Modulus and Cardiac Fibroblast Phenotype in Volume Overload Induced Heart Failure [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480335744116284

    APA Style (7th edition)

  • Childers, Rachel. The Role of Tissue Modulus and Cardiac Fibroblast Phenotype in Volume Overload Induced Heart Failure. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1480335744116284.

    MLA Style (8th edition)

  • Childers, Rachel. "The Role of Tissue Modulus and Cardiac Fibroblast Phenotype in Volume Overload Induced Heart Failure." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480335744116284

    Chicago Manual of Style (17th edition)

osu1480335744116284
688
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This open access ETD is published by The Ohio State University and OhioLINK.