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Ionic, cellular and molecular mechan...

Zhang, Yiqiang.

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Ionic, cellular and molecular mechanisms underlying the QT prolongation and arrhythmias in diabetic cardiocomplications.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Ionic, cellular and molecular mechanisms underlying the QT prolongation and arrhythmias in diabetic cardiocomplications./
Author:	Zhang, Yiqiang.
Description:	280 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 4789.
Contained By:	Dissertation Abstracts International67-09B.
Subject:	Biology, Animal Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NR18050
ISBN:	9780494180501

Ionic, cellular and molecular mechanisms underlying the QT prolongation and arrhythmias in diabetic cardiocomplications.
Zhang, Yiqiang.

Ionic, cellular and molecular mechanisms underlying the QT prolongation and arrhythmias in diabetic cardiocomplications. - 280 p.

Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 4789.

Thesis (Ph.D.)--Universite de Montreal (Canada), 2006.

Heart diseases account for half of all deaths among people with diabetes. Up to one fourth of diabetic patients have prolonged QT interval. QT prolongation, primarily reflecting the lengthening of ventricular action potential duration (APD), can cause sudden cardiac death due to the occurrence of lethal ventricular arrhythmias, and has been considered as a predictor of mortality in both type I and type II diabetic patients. Previous studies found reduction of several ion currents (e.g. reduced Ito and Iss) in experimental models of diabetes. These studies contribute significantly to our current understanding of the ionic mechanisms for diabetic QT prolongation, but several important issues remained unresolved. First, previous studies were conducted nearly exclusively in rats and mice, the species in their adulthood not expressing phenotypic and physiologically significant IKr and IKs that are otherwise the major repolarizing currents determining the plateau phase and total APD in humans. Second, the profiles of changes of ion currents found in rats and mice could hardly fully explain the clinical diabetic QT prolongation. Finally, diabetes is primarily a metabolic disturbance with elevated levels of glucose, reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-alpha) and ceramide, and reduced insulin and impaired insulin signaling transduction. However, these metabolic perturbations as the potential mechanisms for the diabetic electrical disorders have been overlooked in the past.

ISBN: 9780494180501Subjects--Topical Terms:

1017835
Biology, Animal Physiology.

Ionic, cellular and molecular mechanisms underlying the QT prolongation and arrhythmias in diabetic cardiocomplications.
LDR:05314nam 2200313 a 45 001 964068
005 20110901
008 110901s2006 eng d
020 $a 9780494180501
035 $a (UMI)AAINR18050
035 $a AAINR18050
040 $a UMI $c UMI
100 1 $a Zhang, Yiqiang. $3 1287139
245 1 0 $a Ionic, cellular and molecular mechanisms underlying the QT prolongation and arrhythmias in diabetic cardiocomplications.
300 $a 280 p.
500 $a Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 4789.
502 $a Thesis (Ph.D.)--Universite de Montreal (Canada), 2006.
520 $a Heart diseases account for half of all deaths among people with diabetes. Up to one fourth of diabetic patients have prolonged QT interval. QT prolongation, primarily reflecting the lengthening of ventricular action potential duration (APD), can cause sudden cardiac death due to the occurrence of lethal ventricular arrhythmias, and has been considered as a predictor of mortality in both type I and type II diabetic patients. Previous studies found reduction of several ion currents (e.g. reduced Ito and Iss) in experimental models of diabetes. These studies contribute significantly to our current understanding of the ionic mechanisms for diabetic QT prolongation, but several important issues remained unresolved. First, previous studies were conducted nearly exclusively in rats and mice, the species in their adulthood not expressing phenotypic and physiologically significant IKr and IKs that are otherwise the major repolarizing currents determining the plateau phase and total APD in humans. Second, the profiles of changes of ion currents found in rats and mice could hardly fully explain the clinical diabetic QT prolongation. Finally, diabetes is primarily a metabolic disturbance with elevated levels of glucose, reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-alpha) and ceramide, and reduced insulin and impaired insulin signaling transduction. However, these metabolic perturbations as the potential mechanisms for the diabetic electrical disorders have been overlooked in the past.
520 $a In this thesis, we aimed at delineating the underlying ionic, cellular, molecular and signaling mechanisms for diabetic QT prolongation and the associated arrhythmias, and shedding the light on developing novel and rational therapies. We hypothesized that IKr and its pore forming alpha-subunit HERG (human ether-a-go-go related gene) is the major contributor to the diabetic QT prolongation and the impairment of IKr/HERG in diabetic heart is a combined effect of the down-regulation of IKr channel protein and of the negative functional modulation of I Kr/IHERG by metabolic stresses and signaling molecules.
520 $a We reproduced the prolongation of APD and heart-rate corrected QT (QTc) interval in alloxan-induced type 1 diabetic rabbits, and identified the significantly impaired IKr as the major ionic mechanism for diabetic APD prolongation, while other ion currents as the minor contributors to this abnormality. We demonstrated that diabetic metabolic perturbations cause the dysfunction of IKr/HERG in diabetic hearts by significant down-regulation of HERG protein and by impairing IKr/HERG function due to increased levels of ROS, oxidations of lipids and proteins in diabetic myocardium and simultaneously decreased endogenous antioxidant reserve (total antioxidant status), which can be prevented by insulin or vitamin E therapy to decrease the glucose level and/or to reduce the oxidative stress, rendering normalized IKr/HERG function and APD and QTc interval, and preventing the associated arrhythmias.
520 $a Our studies further revealed that the maximum HERG function operates under normoglycemia, and depression of HERG function occurs with either hypoglycemia or hyperglycemia, due to underproduction of ATP in the former, and overproduction of ROS via oxidative phosphorylation in the latter.
520 $a We found that the activity of protein kinase B (PKB), a down-stream component of insulin signaling pathway, is essential for proper function of IKr/HERG. Moreover; TNF-alpha and ceramide, which are known to be deleterious factors critical to the progression of diabetes, both impaired IKr/HERG function via the common pathway, the increases in ROS.
520 $a Based on these data, we conclude that IKr/HERG K+ channelopathy serves as the ionic basis for diabetic QT prolongation and accompanying arrhythmias, and oxidative, stress caused by hyperglycemia as the major metabolic mechanism for diabetic IKr/HERG K+ channelopathy. The dysfunction of IKr/HERG is a combined effect of decrease in the enhancing factors (e.g. insulin, PKB) and increases in the suppressing factors (e.g. hyperglycemia, elevated ROS, TNF-alpha and ceramide). Thus, increasing IKr/IHERG by manipulating HERG expression and by functional modulation on related cellular signaling molecules such as antioxidants could retard and even reverse, at least partially, the electrical disorders in diabetic hearts.
590 $a School code: 0992.
650 4 $a Biology, Animal Physiology. $3 1017835
650 4 $a Biology, Physiology. $3 1017816
690 $a 0433
690 $a 0719
710 2 0 $a Universite de Montreal (Canada). $3 1018132
773 0 $t Dissertation Abstracts International $g 67-09B.
790 $a 0992
791 $a Ph.D.
792 $a 2006
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NR18050