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001 ocn881502189;

003 OCoLC;

005 20141212070344.0;

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008 140619s2014 ncua ob 000 0 eng d;

035 a| (Sirsi) o881502189;

035 a| (OCoLC)881502189;

040 a| EREe| rdac| EREd| UtOrBLW;

049 a| EREE;

100 1 a| Mattox, Taylor Ann,e| author.?| UNAUTHORIZED;

245 10 a| Discovery and investigation of a novel role for mitochondrial prohibitin in mitigating acute heart failure in endotoxic shock /c| by Taylor Ann Mattox.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2014.;

300 a| 229 pages :b| illustrations (some color);

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text fileb| PDFc| 4.77Mb2| rda;

490 1 a| ECU Brody School of Medicine thesis;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| Ph.D.c| East Carolina Universityd| 2014.;

500 a| Presented to the faculty of the Department of Pharmacology and Toxicology.;

500 a| Advisor: Ethan J. Anderson.;

500 a| Title from PDF t.p. (viewed June 18, 2014).;

504 a| Includes bibliographical references.;

650 2 a| Sepsisx| metabolism.=| ^A1204823;

650 2 a| Multiple Organ Failure.=| ^A952507;

650 2 a| Heart Failure.=| ^A919098;

650 2 a| Repressor Proteinsx| metabolism.=| ^A1203872;

650 2 a| Mitochondriax| metabolism.=| ^A933426;

653 a| Pharmacology;

653 a| Biochemistry;

653 a| Physiology;

700 1 a| Anderson, Ethan J.,e| degree supervisor.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Pharmacology and Toxicology.?| UNAUTHORIZED;

830 0 a| ECU Brody School of Medicine thesis.=| ^A964744;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/4428;

880 3 6| 520-00a| Sepsis results in more than 200,000 deaths annually and is the 10th leading cause of death in the United States (US). In spite of significant advances in medical care the mortality rate for sepsis has continued to rise. Sepsis and the diseases along its continuum (septic shock and multiple organ dysfunction syndrome, MODS) are characterized by excessive production of inflammatory mediators via a feed-forward mechanism that results in a condition commonly referred to as the `cytokine storm.' This maladaptive inflammatory response, and the subsequent mitochondrial dysfunction that results from it, are thought to underlie the impairment of cardiac function that occurs in the progression from sepsis to MODS. Prohibitin (PHB) is a ubiquitously expressed mitochondrial localized protein, which recent evidence has suggested has a wide variety of roles from transcriptional regulator to a mediator of inflammatory and oxidative signaling. Here, using a comprehensive series of in vitro and in vivo experiments, we tested the hypothesis that PHB confers cardiac protection during endotoxic shock (i.e., cytokine storm induced by LPS) through 1) preservation of mitochondrial integrity 2) attenuated inflammatory signaling, primarily through NFκB and 3) augmented Nrf2 signaling and antioxidant capacity. As expected, LPS and cytokines disrupted mitochondrial function and integrity in both our models. In rats, LPS injection reduced PHB expression in whole heart while simultaneously concentrating the remainder in the nucleus. Interestingly, serum levels of PHB were transiently elevated 3-fold by LPS, but were restored to normal levels within 24 hours. Similarly, whole cell PHB expression was reduced and nuclear accumulation of PHB was increased in cardiomyocytes following TNFα/IL1β treatment in vitro. Overexpression of PHB (oPHB) and treatment with recombinant PHB (rPHB) protected cardiomyocytes from TNFα/IL1β-induced toxicity by preserving mitochondrial function, suppressing oxidative stress and ultimately mitigating cytokine-induced cytotoxicity. We further observed that oPHB and rPHB attenuated the TNFα/IL1β-induced transcription of pro-inflammatory genes in cardiomyocytes, while augmenting Nrf2 nuclear transactivation and up-regulation of Nrf2-mediated genes. Next, using wild-type (WT) and Nrf2-/- mice we tested the hypothesis that cytokine generation and inflammatory signaling induced by LPS challenge would be suppressed by rPHB treatment in a Nrf2-dependent manner, leading to protection of cardiac mitochondria and recovery of cardiac function. Following LPS challenge, endogenous levels of PHB transiently increased dramatically in WT but not Nrf2-/- mice. Treatment with rPHB following LPS challenge suppressed circulating levels of IL6 and TNFα in WT and Nrf2-/- mice, resulting in decreased NFκB and STAT3 activation in heart and complete attenuation of proinflammatory cytokines and iNOS in this organ. Additionally, rPHB treatment reversed the LPS-induced decrease in mitochondrial ATP generation in heart, simultaneously leading to rapid recovery of cardiac function within ~12 hours. Interestingly, rPHB treatment mitigated the LPS-induced inflammatory response and cardiac dysfunction to similar extent in both WT and Nrf2-/- mice, suggesting the effects of rPHB are independent of Nrf2. Collectively, these findings suggest that PHB is a mitochondrial inner-membrane protein that acts as a mobile signal transducer, capable of moving from mitochondria to nucleus and also between cell and tissue compartments, to suppress inflammation and cytotoxicity during severe inflammatory stress. They further suggest that PHB may be critical to alleviating the maladapative host response to infection and represents a novel therapeutic target for the treatment of sepsis-associated cardiac dysfunction. Future studies directed at exploiting the pleiotropic functions of PHB to mitigate inflammation and oxidative stress in other cardio-metabolic disease models will be important to building on the knowledge that the present studies have established.;

949 a| Click on web addressw| ASISh| JOYNER101;

949 a| Click on web addressw| ASISh| HSL111;

949 o| jdjr;

994 a| C0b| ERE;

096 a| WC 240;

596 a| 1 4;

998 a| 3486170;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 3486170-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 6/19/2014x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 3486170-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 6/19/2014x| ETDz| HERESOURCE;

Discovery and investigation of a novel role for mitochondrial prohibitin in mitigating acute heart failure in endotoxic shock / by Taylor Ann Mattox.

Author/creator	Mattox, Taylor Ann author.
Other author	Anderson, Ethan J., degree supervisor.
Other author	East Carolina University. Department of Pharmacology and Toxicology.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2014.
Description	229 pages : illustrations (some color)
Supplemental Content	Access via ScholarShip
Subjects	Sepsis--metabolism. Multiple Organ Failure. Heart Failure. Repressor Proteins--metabolism. Mitochondria--metabolism.

Series	ECU Brody School of Medicine thesis ECU Brody School of Medicine thesis. ^A964744
General note	Presented to the faculty of the Department of Pharmacology and Toxicology.
General note	Advisor: Ethan J. Anderson.
General note	Title from PDF t.p. (viewed June 18, 2014).
Dissertation note	Ph.D. East Carolina University 2014.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Discovery and investigation of a novel role for mitochondrial prohibitin in mitigating acute heart failure in endotoxic shock / by Taylor Ann Mattox.

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