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The Role of MMP-13 in Cardiac Remodeling and Fibrosis

Schafer, Allison E
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1537949351943938

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
Heart failure (HF) is the leading cause of morbidity and mortality in the United States and is characterized by progressive pathologic remodeling, fibrosis and deteriorating cardiac function. Cardiac fibrosis occurs due to an imbalance in the production and degradation of the extracellular matrix (ECM). Cardiac fibroblasts (CF) are largely responsible for the secretion of ECM proteins in the heart. Upon injury or pathologic stimulation, CF transition to a pathologic myofibroblast phenotype, leading to excess production of ECM proteins and pro-inflammatory cytokines. Elevated expression of matrix metalloproteinases (MMPs), proteolytic enzymes responsible for maintenance and degradation of the ECM, is common in HF. Specifically, MMP-13, one of the major interstitial collagenases in both mice and humans, is known to be upregulated in human HF patients as well as animal models of HF. However, few studies have been performed to elucidate the role of MMP-13 in the heart. Further, while CF are considered the main cellular source of MMPs in the heart, MMP-13 has been shown to be expressed in multiple cell types. Therefore, the goal of this dissertation was to determine the role of MMP-13 in a long-term model of HF as well as examine the cell specific source and role of MMP-13 in the heart. Utilizing a selective MMP-13 inhibitor, we show, for the first time, a role for MMP-13 in the myofibroblast phenotype and in the development and progression of ventricular remodeling and failure after injury. Specifically, inhibition of MMP-13 attenuates myofibroblast invasion, migration and proliferation, suggesting that MMP-13 inhibition reduces the pathologic phenotype of these cells. Additionally, mice that were treated with the MMP-13 inhibitor 4 weeks after injury display significant improvement in cardiac function compared to control animals after cardiac injury with concomitant attenuation in cardiac hypertrophy. Further, mice treated with the MMP-13 inhibitor have significantly reduced fibrotic remodeling compared to control mice. CF are considered the major contributors of MMPs, including MMP-13, in the heart. To gain a better understanding the cell specific contribution of MMP-13, novel cell specific MMP-13 knockout mice, in which MMP-13 was ablated from cardiomyocytes (CM; CM-MMP13KO) or myofibroblasts (MF; MF-MMP13KO), were generated and subjected to cardiac injury. We observed no significant changes in cardiac function in CM-MMP13KO mice. However, MF-MMP13KO mice display attenuated cardiac hypertrophy with preserved cardiac function, despite having an exacerbated fibrotic response after injury, and this may be due to specific alterations in interstitial fibrosis in these animals. The data presented in this dissertation suggests that MMP-13 contributes to cardiac remodeling, dysfunction and fibrosis in a long-term model of HF. Further, MMP-13 contributes to the pathological myofibroblasts phenotype, which plays a major role in the development of HF. Future studies will allow for the better understanding of the mechanism behind MMP-13-mediated changes in ECM, whether through alterations in collagen organization or receptor signaling. Overall, the data suggest a therapeutic potential for MMP-13 as a novel target in the treatment of HF.
Burns Blaxall, Ph.D. (Committee Chair)
Evangelia Kranias, Ph.D. (Committee Member)
Jo El Schultz, Ph.D. (Committee Member)
Katherine Yutzey, Ph.D. (Committee Member)
180 p.
Pharmacology
Heart failure; Fibrosis; Cardiac fibroblast; MMP

Recommended Citations

Citations

  • Schafer, A. E. (2018). The Role of MMP-13 in Cardiac Remodeling and Fibrosis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1537949351943938

    APA Style (7th edition)

  • Schafer, Allison. The Role of MMP-13 in Cardiac Remodeling and Fibrosis. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1537949351943938.

    MLA Style (8th edition)

  • Schafer, Allison. "The Role of MMP-13 in Cardiac Remodeling and Fibrosis." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1537949351943938

    Chicago Manual of Style (17th edition)

ucin1537949351943938
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© 2018, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.
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