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Hsp70.1 contributes to the NF-κB paradox after myocardial ischemic insults

Wilhide, Michael

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2010, MS, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.

One of the leading causes of death globally is cardiovascular disease, with most of these deaths related to myocardial ischemia. Myocardial ischemia and reperfusion causes several biochemical and metabolic changes that result in the activation of transcription factors that are involved in cell survival and cell death. The transcription factor Nuclear Factor-Kappa B (NF-κB) is associated with cardioprotection (e.g. after permanent coronary occlusion, PO) and cell injury (e.g. after ischemia/reperfusion, I/R). However, there is a lack of knowledge regarding how NF-κB mediates cell survival vs. cell death after ischemic insults, preventing the identification of novel therapeutic targets for enhanced cardioprotection and decreased injurious effects.

The objective of this thesis is to distinguish and determine the mechanisms underlying the differential effects of NF-κB following ischemic insults. For example, NF-κB-dependent cardioprotection after PO vs. NF-κB-dependent cell death after I/R. It is hypothesized that NF-κB is a key signaling integrator that differentially regulates distinct sets of NF-κB-dependent genes that contribute to cardioprotection or cell death after ischemic insults. Transgenic mice were used, in which NF-κB activation is genetically blocked in the cardiomyocytes (DN), along with gene expression assays (e.g. microarrays and quantitative real-time PCR (QRT-PCR)) to determine sets of genes that may contribute to cardioprotection and cell death.

Our results identified 16 genes both up- and down-regulated by NF-κB and after PO, which may contribute to NF-κB-dependent cardioprotection after PO. In addition, our results revealed 59 genes both up- and down-regulated by NF-κB and after I/R, which may result in NF-κB-dependent cell death after I/R. The main objective is to identify genes that are dysregulated (up- and down-regulated) between PO and I/R (16 genes regulated by NF-κB and PO vs. 59 genes regulated by NF-κB and I/R). Only one gene was significantly up-regulated by NF-κB after PO and I/R, which is heat shock protein 90kDa alpha (cytosolic), class A member 1 (hsp90aa1). However, heat shock protein 1A (hspa1a/hsp70.3) and heat shock protein 1B (hspa1b/hsp70.1) genes are highly up-regulated in response to both ischemic insults. NF-κB significantly up-regulated hspa1a after PO and hspa1a and hspa1b after I/R. QRT-PCR confirmed that hspa1a and hspa1b genes are highly up-regulated by both ischemic insults and up-regulated by NF-κB.

In general, heat shock proteins 70 are known to be involved in cell survival and cell death outcomes. However, there is a lack of information regarding the individual role of Hsp70.1 and Hsp70.3 after myocardial ischemic insults. Therefore, Hsp70.1 and Hsp70.3 were investigated by using Hsp70.1/Hsp70.3 double knockout mice and Hsp70.1 single knockout mice. Interestingly, our results show that Hsp70.1 provided cardioprotection after PO, in contrast to causing cell injury after I/R; whereas, Hsp70.3 may provide cardioprotection after I/R.

The significance of the research is the identification of unique sets of genes that may underlie the NF-κB paradox. The novel findings of the thesis are that Hsp70.1 underlies NF-κB-dependent cardioprotection after PO and NF-κB-dependent cell injurious effects after I/R. Our results contribute to the understanding of how NF-κB differentially regulates cell survival versus cell death effects after ischemic stimuli.

Walter Keith Jones, PhD (Committee Chair)
Muhammad Ashraf, PhD (Committee Member)
Mohammed Matlib, PhD (Committee Member)
Jo El Schultz, PhD (Committee Member)
Basilia Zingarelli, MD, PhD (Committee Member)
232 p.

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Citations

  • Wilhide, M. (2010). Hsp70.1 contributes to the NF-κB paradox after myocardial ischemic insults [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282575234

    APA Style (7th edition)

  • Wilhide, Michael. Hsp70.1 contributes to the NF-κB paradox after myocardial ischemic insults. 2010. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282575234.

    MLA Style (8th edition)

  • Wilhide, Michael. "Hsp70.1 contributes to the NF-κB paradox after myocardial ischemic insults." Master's thesis, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282575234

    Chicago Manual of Style (17th edition)