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Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease

Schwanekamp, Jennifer A
http://orcid.org/0000-0002-0329-5786
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803264229101

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
Deposition, maturation, and regulation of the extracellular matrix (ECM) are key components of the overall fibrotic response, which plays a major pathological role in many forms of cardiovascular disease (CVD). Paradoxically, ECM remodeling is also required for preserving ventricular chamber integrity after injury and for maintaining vessel compliance and structure under physiological conditions. However, excessive and dysregulated ECM deposition occurs during disease, such as vessel wall remodeling during atherosclerosis or the replacement of dying cardiomyocytes by noncompliant scar tissue in the setting of myocardial infarction (MI). Although the molecular players that regulate pathological ECM remodeling are still poorly understood, one superfamily known as the matricellular proteins, a group of stress-induced ECM modulators, has received particular attention. Here we investigated the roles played by two matricellular protein family members, periostin and transforming growth factor beta induced (TGFBI), in mouse models of atherosclerosis, coronary artery disease (CAD) and hypertensive heart disease (HHD). Periostin and TGFBI are known to interact directly with a number of ECM proteins and have roles in cell adhesion and migration, two essential components of the fibrotic response. We first investigated the role periostin plays in atherosclerotic plaque development. Using a well-characterized model of atherosclerosis, the ApoE knockout mouse (ApoE-/-), we show that periostin is induced within the plaque and also in the circulating blood, suggesting a role for periostin in disease progression. Using a periostin-deficient global knockout mouse model crossed to the ApoE-/- mouse, we find that loss of periostin reduces plaque burden through a mechanism involving decreased collagen maturation within the plaque and impaired macrophage recruitment. We then investigated the role of TGFBI, a paralog of periostin, in ventricular remodeling in the heart after injury. Because periostin and TGFBI share significant structural and amino acid similarity, we hypothesized that TGFBI may have overlapping functions with periostin. To test this, we used a mouse model with genetic deletion of TGFBI and found that loss of this gene did not alter disease pathology after MI, suggesting that periostin may be able to compensate for loss of TGFBI. To further test this, we generated mice deficient for both TGFBI and periostin; however, combined deletion of TGFBI and periostin did not worsen disease pathology after MI beyond what was observed with periostin deletion, suggesting that periostin is the main indicator of pathological remodeling after injury in the heart. The data presented in this thesis suggest that periostin is not only a main effector in ECM remodeling in the heart in response to injury, but that it also plays a dominant role over TGFBI, in addition to being a significant contributor to atherosclerotic disease progression. Future studies that dissect the regulatory elements that control expression of periostin or TGFBI in response to injury should suggest the therapeutic potential of modulating these matricellular proteins in cardiovascular disease.
Jeffery Molkentin, Ph.D. (Committee Chair)
Burns Blaxall, Ph.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
Thomas Thompson, Ph.D. (Committee Member)
David Wieczorek, Ph.D. (Committee Member)
136 p.
Molecular Biology
extracellular matrix; cardiovascular disease; atherosclerosis; periostin; TGFBI; fibrosis

Recommended Citations

Citations

  • Schwanekamp, J. A. (2017). Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803264229101

    APA Style (7th edition)

  • Schwanekamp, Jennifer. Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803264229101.

    MLA Style (8th edition)

  • Schwanekamp, Jennifer. "Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803264229101

    Chicago Manual of Style (17th edition)

ucin1504803264229101
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This open access ETD is published by University of Cincinnati and OhioLINK.