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003 OCoLC;

005 20191023085848.0;

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035 a| (Sirsi) o1105587045;

035 a| (OCoLC)1105587045;

049 a| EREE;

100 1 a| Leffler, Korin Eileen,e| author.?| UNAUTHORIZED;

245 10 a| Disrupted adiponectin-connexin43 signaling underlies exacerbated myocardial dysfunction in diabetic female rats /c| by Korin Eileen Leffler.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2019.;

300 a| 141 pages :b| illustrations.;

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text fileb| PDFc| 2.515 MB2| rda;

490 1 a| ECU Brody School of Medicine dissertation;

538 a| System requirements: Adobe Reader.;

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

502 b| Ph.D.c| East Carolina Universityd| 2019.;

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

500 a| Advisor: Abdel A. Abdel-Rahman;

500 a| Title from PDF t.p. (viewed August 19, 2019).;

520 3 a| The 2015 American Heart Association scientific statement has advocated for sex- specific research to understand the paradoxically higher sensitivity of women to type 2 diabetes mellitus (T2DM)-associated cardiovascular morbidity and mortality. The primary goal of this study was to address this need by elucidating the mechanisms by which these females lose inherent cardioprotection and become more susceptible to detrimental cardiovascular-related outcomes than males. The central hypothesis of this study was "estrogen (E2) exacerbation of diabetes-evoked disruption of cardiac adiponectin (APN)-connexin 43 (Cx43) signaling underlies heightened myocardial dysfunction in diabetic females". The study provides novel data on the modulation of the cardiac E2-APN-Cx43 axis and its critical role in maintaining a delicate redox balance in cardiomyocytes, how this cardioprotective signaling becomes detrimental in T2DM, and identified a molecular target for developing potential pharmacological interventions for diabetic females. Our findings demonstrate that E2 exacerbates female autonomic and cardiac dysfunction in a rodent model of T2DM, increasing left ventricular (LV) mass and Tau as well as decreasing LVDP, dP/dtmax, dP/dtmin, contractility index (CI) and fractional shortening (FS). Additionally, the restoration of the APN-Cx43 signaling axis via a small molecule APN agonist virtually reverses all of these cardiac dysfunction parameters as well as mitigates detrimental molecular alterations and a proinflammatory milieu in all female rats by restoring cardiac levels of Cx43, decreasing heme oxygenase 1 (HO-1), tumor necrosis factor (TNF) [alpha] and circulating levels of asymmetric dimethylarginine (ADMA). The research project replicates the unexplained paradoxically higher mortality risk in women and provides novel mechanisms for this cardiovascular health problem. Collectively, these findings support the hypothesis and proposed underlying mechanism and further demonstrations that the restoration of Cx43 emerges as a promising novel target in diabetic cardiovascular disease for the development of future therapeutics for women.;

504 a| Includes bibliographical references.;

650 2 a| Signal Transduction.=| ^A925743;

650 2 a| Rats.=| ^A918924;

650 2 a| Animals.=| ^A919771;

650 2 a| ADIPOQ protein, human.?| UNAUTHORIZED;

650 2 a| Adiponectin.=| ^A1205418;

650 2 a| GJA1 protein, human.?| UNAUTHORIZED;

650 2 a| Connexin 43.=| ^A1385838;

650 2 a| Cardiomyopathies.=| ^A948202;

650 2 a| Receptors, Adiponectin.=| ^A1385871;

653 a| Estrogen;

653 a| sex differences;

653 a| cardiovascular pharmacology;

700 1 a| Abdel-Rahman, Abdel A.,e| degree supervisor.=| ^A1419660;

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

830 0 a| ECU Brody School of Medicine dissertation.?| UNAUTHORIZED;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/7206;

949 o| wjh;

994 a| C0b| ERE;

096 a| QU 375;

596 a| 1 4;

998 a| 5111025;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 5111025-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 6/24/2019x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 5111025-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 6/24/2019x| ETDz| HERESOURCE;

Disrupted adiponectin-connexin43 signaling underlies exacerbated myocardial dysfunction in diabetic female rats / by Korin Eileen Leffler.

Author/creator	Leffler, Korin Eileen author.
Other author	Abdel-Rahman, Abdel A., degree supervisor.
Other author	East Carolina University. Department of Pharmacology and Toxicology.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2019.
Description	141 pages : illustrations.
Supplemental Content	Access via ScholarShip
Subjects	Signal Transduction. Rats. Animals. ADIPOQ protein, human. Adiponectin. GJA1 protein, human. Connexin 43. Cardiomyopathies. Receptors, Adiponectin.

Series	ECU Brody School of Medicine dissertation ECU Brody School of Medicine dissertation. UNAUTHORIZED
Summary	The 2015 American Heart Association scientific statement has advocated for sex- specific research to understand the paradoxically higher sensitivity of women to type 2 diabetes mellitus (T2DM)-associated cardiovascular morbidity and mortality. The primary goal of this study was to address this need by elucidating the mechanisms by which these females lose inherent cardioprotection and become more susceptible to detrimental cardiovascular-related outcomes than males. The central hypothesis of this study was "estrogen (E2) exacerbation of diabetes-evoked disruption of cardiac adiponectin (APN)-connexin 43 (Cx43) signaling underlies heightened myocardial dysfunction in diabetic females". The study provides novel data on the modulation of the cardiac E2-APN-Cx43 axis and its critical role in maintaining a delicate redox balance in cardiomyocytes, how this cardioprotective signaling becomes detrimental in T2DM, and identified a molecular target for developing potential pharmacological interventions for diabetic females. Our findings demonstrate that E2 exacerbates female autonomic and cardiac dysfunction in a rodent model of T2DM, increasing left ventricular (LV) mass and Tau as well as decreasing LVDP, dP/dtmax, dP/dtmin, contractility index (CI) and fractional shortening (FS). Additionally, the restoration of the APN-Cx43 signaling axis via a small molecule APN agonist virtually reverses all of these cardiac dysfunction parameters as well as mitigates detrimental molecular alterations and a proinflammatory milieu in all female rats by restoring cardiac levels of Cx43, decreasing heme oxygenase 1 (HO-1), tumor necrosis factor (TNF) [alpha] and circulating levels of asymmetric dimethylarginine (ADMA). The research project replicates the unexplained paradoxically higher mortality risk in women and provides novel mechanisms for this cardiovascular health problem. Collectively, these findings support the hypothesis and proposed underlying mechanism and further demonstrations that the restoration of Cx43 emerges as a promising novel target in diabetic cardiovascular disease for the development of future therapeutics for women.
General note	Presented to the faculty of the Department of Pharmacology and Toxicology
General note	Advisor: Abdel A. Abdel-Rahman
General note	Title from PDF t.p. (viewed August 19, 2019).
Dissertation note	Ph.D. East Carolina University 2019.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Disrupted adiponectin-connexin43 signaling underlies exacerbated myocardial dysfunction in diabetic female rats / by Korin Eileen Leffler.

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