Atherosclerosis is the leading cause of death among all age-related diseases. One potential way to attenuate aging is to reduce the accumulation of aging cells, also called senescent cells. Our lab previously reported that zinc overload and deletion of zinc transporters contribute to senescence development in vascular smooth muscle cells (VSMCs). However, the detailed mechanism remains unclear. Autophagy, a protective mechanism removing dysfunctional organelles and proteins, has been reported to delay senescence development. However, it is unknown whether the upregulation of autophagy by zinc and zinc transporters is required for the inhibition of senescence. Additionally, p62, an autophagy adaptor degraded through autophagy, has been reported to attenuate senescence in mice. However, it remains unknown whether p62 levels are regulated by zinc or zinc transporters. In this dissertation, we found that in HEK293 cells, zinc stimulated autophagy and inhibited proteasome degradation. However, p62 level was increased by zinc. Zinc changed the location of p62 and protected p62 from degradation. Similarly, overexpression of zinc transporters (ZnT), especially ZnT3, stimulated autophagy and increased the p62 level. Additionally, ZnT3 interacted with p62 and protected p62 from degradation pathways. In vascular smooth muscle cells isolated from aortas of mice (MASMs), zinc and overexpression of ZnT3 also upregulated autophagy. Lack of ZnT3 or p62 in MASMs contributed to defective autophagy and increased senescence. Similarly, ZnT3-/- mice present a higher senescence level and an increased level of p62, suggesting that autophagy is downregulated in ZnT3-/- mice. Male ApoE-/-ZnT3-/- mice fed with high fat diet (HFD) had more plaque suggesting ZnT3 is important in atherosclerosis in the male. However, atherosclerosis level was not affected by HFD in female ApoE-/-ZnT3-/- mice. Overall, in this dissertation, we uncovered a new role of ZnT3 as a critical regulator of autophagy, vascular senescence, and atherosclerosis. / A Dissertation submitted to the Department of Nutrition, Food and Exercise Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester 2018. / June 14, 2018. / Autophagy, Vascular Senescence, Zinc, Zinc transporters / Includes bibliographical references. / Gloria Salazar, Professor Directing Dissertation; Cathy W. Levenson, University Representative; Bahram H. Arjmandi, Committee Member; Shridhar K. Sathe, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_650760 |
| Contributors | Zhao, Yitong (author), Salazar, Gloria (professor directing dissertation), Levenson, Cathy W. (university representative), Arjmandi, Bahram H (committee member), Sathe, Shridhar K. (committee member), Florida State University (degree granting institution), College of Human Sciences (degree granting college), Department of Nutrition, Food, and Exercise Science (degree granting departmentdgg) |
| Publisher | Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text, doctoral thesis |
| Format | 1 online resource (113 pages), computer, application/pdf |
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