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Cardiac specific haploinsufficiency of β-catenin attenuates cardiac hypertrophy from aortic constriction
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Abstracts / Journal of Molecular and Cellular Cardiology 41 (2006) 732 – 751
stressed senescent myocardium. We assessed the effect of MPM therapy, being preoperative CoQ10 with additional antioxidants and cellular energisers (metabolic therapy), together with exercise and mental stress reduction (holistic) therapy in a randomised clinical trial. Aims: To assess the effect of MPM therapy on: 1. Oxidative stress; 2. Incidence of complications; 3. Length of stay in hospital; 4. Quality of life. Methods: Patients undergoing elective CABG or valve surgery were randomised to one of four treatment groups: 1. Metabolic; 2. Holistic; 3. Both; or 4. Neither. Metabolic therapy comprised CoQ10, magnesium orotate, alpha-lipoic acid, omega-3 fatty acids and selenium. Holistic therapy comprised two 120-minute sessions per week. Patients were on therapy for a minimum of 2 weeks prior to surgery. Biochemical and clinical data were obtained. Results: Seventy-two patients were included in this interim analysis. Metabolic therapy versus placebo: differences were found in the 24-h postoperative plasma troponin I level (1.0 vs 1.8 Ag/L, p = 0.02), incidence of postoperative atrial fibrillation (15.8% vs 38.2%, p = 0.03) and length of postoperative hospital stay (5.0 vs 7.0 days, p = 0.007). Holistic therapy versus no holistic therapy: no differences were identified. Conclusions: The interim analysis suggests that metabolic therapy before cardiac surgery is associated with: 1. Reduced myocardial damage as assessed by troponin I release; 2. Reduced incidence of postoperative atrial fibrillation; 3. Shortened length of hospital stay. doi:10.1016/j.yjmcc.2006.06.034
21. Cardiac specific haploinsufficiency of B-catenin attenuates cardiac hypertrophy from aortic constriction Xian Ping Yi*, Jiaxiang Qu, Jibin Zhou, Xuejun Wang, Faqian Li. Cardiovascular Research Institute, Department of Pathology, Zhongshan University the Fifth Affiliated Hospital, Guangdong Province, P. R. China In addition to its role in cell-cell adhesion, h-catenin is an important signaling molecule in the Wnt/Wingless pathway. Recent studies have also indicated that the h-catenin is stabilized during cardiac hypertrophy. The direct role of the h-catenin in cardiac remodeling and myocyte shape regulation during cardiac hypertrophy, however, remains to be investigated. Since the global deletion of h-catenin is embryonically lethal, we have deleted h-catenin genes specifically in cardiac myocytes by crossing loxP-flanked h-catenin mice with transgenic mice expressing a Cre protein under the control of the a-myosin heavy chain promoter. No homozygous loxPflanked h-catenin mice positive for the Cre were born alive, indicating the complete deletion of h-catenin in cardiac myocytes is embryonically lethal. Heterozygous h-catenin deleted mice, however, demonstrated no structural and functional abnormality. The response of heterozygous hcatenin deleted mice to aortic constriction was significantly attenuated with decreased heart weight and heart weight/body
weight ratio compared to wild type controls. Morphometric data further demonstrated that cardiac myocytes from heterozygous knockout mice had smaller volume and diameter. On the other hand, the expression of fetal genes, h-myosin heavy chain, atrial and brain natriuretic peptides were significantly higher in heterozygous h-catenin deleted mice when compared to wild type mice. doi:10.1016/j.yjmcc.2006.06.035
22. Differential distribution of the stretch sensitive K channels TREK-1 and TRAAK in the adult rat heart L. Mackenzie *, D. Saint. University of Adelaide, Adelaids, SA, Australia Mechanical forces on the myocardium can alter the action potential via activation of mechano-sensitive ion channels, a process called mechano-electric feedback (MEF). It is well known that certain other potassium channels are differentially distributed in the myocardium resulting in different action potential morphology between, for example, epicardium and endocardium, a difference thought to be important for the control of arrhythmias. What is not known is if the mechanosensitive channels are also differentially expressed in the heart. This immunohistochemical study was designed to demonstrate the distribution of the two-pore mechano-sensitive potassium channels, TREK-1 and TRAAK, in the ventricular walls of the normal rat heart. Under anaesthesia, hearts were removed from adult Sprague Dawley rats (n = 5 for each group) and perfused via the aorta with Tyrode’s solution followed by Bouin’s Fixative solution. Hearts were postfixed overnight then horizontal 35 Am vibratome sections were cut from various levels of the heart. Immunohistochemistry for TREK-1 and TRAAK was performed using rabbit polyclonal antibodies raised for each of the channels against an epitope near the C-terminus. Both the nickel-enhanced glucose oxidase diaminobenzidine reaction (God-DAB) and fluorescent labelling were used to visualise the specific binding. TREK-1 and TRAAK immunoreactivity patterns were mapped throughout the ventricular walls of the heart (40,100 and 200 magnifications). Both TREK-1 and TRAAK were differentially distributed not only through the left and right free ventricular walls and the septum but also at different levels of the heart from apex to base. Immunohistochemical staining of isolated ventricular myocytes confirmed the presence of TREK-1 and TRAAK channels. We propose that this pattern of differential distribution of TREK-1 and TRAAK channels throughout the rat ventricles leads to a spatially heterogeneous electrophysiological response to stretch in myocardium. This may be important in protecting against dispersion of repolarisation and the formation of arrhythmias when the heart is subject to abnormal stresses. doi:10.1016/j.yjmcc.2006.06.036
Abstracts / Journal of Molecular and Cellular Cardiology 41 (2006) 732 – 751
stressed senescent myocardium. We assessed the effect of MPM therapy, being preoperative CoQ10 with additional antioxidants and cellular energisers (metabolic therapy), together with exercise and mental stress reduction (holistic) therapy in a randomised clinical trial. Aims: To assess the effect of MPM therapy on: 1. Oxidative stress; 2. Incidence of complications; 3. Length of stay in hospital; 4. Quality of life. Methods: Patients undergoing elective CABG or valve surgery were randomised to one of four treatment groups: 1. Metabolic; 2. Holistic; 3. Both; or 4. Neither. Metabolic therapy comprised CoQ10, magnesium orotate, alpha-lipoic acid, omega-3 fatty acids and selenium. Holistic therapy comprised two 120-minute sessions per week. Patients were on therapy for a minimum of 2 weeks prior to surgery. Biochemical and clinical data were obtained. Results: Seventy-two patients were included in this interim analysis. Metabolic therapy versus placebo: differences were found in the 24-h postoperative plasma troponin I level (1.0 vs 1.8 Ag/L, p = 0.02), incidence of postoperative atrial fibrillation (15.8% vs 38.2%, p = 0.03) and length of postoperative hospital stay (5.0 vs 7.0 days, p = 0.007). Holistic therapy versus no holistic therapy: no differences were identified. Conclusions: The interim analysis suggests that metabolic therapy before cardiac surgery is associated with: 1. Reduced myocardial damage as assessed by troponin I release; 2. Reduced incidence of postoperative atrial fibrillation; 3. Shortened length of hospital stay. doi:10.1016/j.yjmcc.2006.06.034
21. Cardiac specific haploinsufficiency of B-catenin attenuates cardiac hypertrophy from aortic constriction Xian Ping Yi*, Jiaxiang Qu, Jibin Zhou, Xuejun Wang, Faqian Li. Cardiovascular Research Institute, Department of Pathology, Zhongshan University the Fifth Affiliated Hospital, Guangdong Province, P. R. China In addition to its role in cell-cell adhesion, h-catenin is an important signaling molecule in the Wnt/Wingless pathway. Recent studies have also indicated that the h-catenin is stabilized during cardiac hypertrophy. The direct role of the h-catenin in cardiac remodeling and myocyte shape regulation during cardiac hypertrophy, however, remains to be investigated. Since the global deletion of h-catenin is embryonically lethal, we have deleted h-catenin genes specifically in cardiac myocytes by crossing loxP-flanked h-catenin mice with transgenic mice expressing a Cre protein under the control of the a-myosin heavy chain promoter. No homozygous loxPflanked h-catenin mice positive for the Cre were born alive, indicating the complete deletion of h-catenin in cardiac myocytes is embryonically lethal. Heterozygous h-catenin deleted mice, however, demonstrated no structural and functional abnormality. The response of heterozygous hcatenin deleted mice to aortic constriction was significantly attenuated with decreased heart weight and heart weight/body
weight ratio compared to wild type controls. Morphometric data further demonstrated that cardiac myocytes from heterozygous knockout mice had smaller volume and diameter. On the other hand, the expression of fetal genes, h-myosin heavy chain, atrial and brain natriuretic peptides were significantly higher in heterozygous h-catenin deleted mice when compared to wild type mice. doi:10.1016/j.yjmcc.2006.06.035
22. Differential distribution of the stretch sensitive K channels TREK-1 and TRAAK in the adult rat heart L. Mackenzie *, D. Saint. University of Adelaide, Adelaids, SA, Australia Mechanical forces on the myocardium can alter the action potential via activation of mechano-sensitive ion channels, a process called mechano-electric feedback (MEF). It is well known that certain other potassium channels are differentially distributed in the myocardium resulting in different action potential morphology between, for example, epicardium and endocardium, a difference thought to be important for the control of arrhythmias. What is not known is if the mechanosensitive channels are also differentially expressed in the heart. This immunohistochemical study was designed to demonstrate the distribution of the two-pore mechano-sensitive potassium channels, TREK-1 and TRAAK, in the ventricular walls of the normal rat heart. Under anaesthesia, hearts were removed from adult Sprague Dawley rats (n = 5 for each group) and perfused via the aorta with Tyrode’s solution followed by Bouin’s Fixative solution. Hearts were postfixed overnight then horizontal 35 Am vibratome sections were cut from various levels of the heart. Immunohistochemistry for TREK-1 and TRAAK was performed using rabbit polyclonal antibodies raised for each of the channels against an epitope near the C-terminus. Both the nickel-enhanced glucose oxidase diaminobenzidine reaction (God-DAB) and fluorescent labelling were used to visualise the specific binding. TREK-1 and TRAAK immunoreactivity patterns were mapped throughout the ventricular walls of the heart (40,100 and 200 magnifications). Both TREK-1 and TRAAK were differentially distributed not only through the left and right free ventricular walls and the septum but also at different levels of the heart from apex to base. Immunohistochemical staining of isolated ventricular myocytes confirmed the presence of TREK-1 and TRAAK channels. We propose that this pattern of differential distribution of TREK-1 and TRAAK channels throughout the rat ventricles leads to a spatially heterogeneous electrophysiological response to stretch in myocardium. This may be important in protecting against dispersion of repolarisation and the formation of arrhythmias when the heart is subject to abnormal stresses. doi:10.1016/j.yjmcc.2006.06.036