- MeSH
- Diabetes Mellitus, Type 1 MeSH
- Ventricular Fibrillation MeSH
- Financing, Organized MeSH
- Fluorescent Antibody Technique MeSH
- Phosphorylation MeSH
- Hypertension MeSH
- Hyperthyroidism MeSH
- Connexin 43 physiology metabolism MeSH
- Animals, Laboratory MeSH
- Gap Junctions drug effects MeSH
- Cell Communication MeSH
- Disease Models, Animal MeSH
- Rats, Wistar MeSH
- Gene Expression Regulation MeSH
- Heart innervation MeSH
- Arrhythmias, Cardiac mortality MeSH
- Statistics as Topic MeSH
- Check Tag
- Male MeSH
Genetic component represents an important factor in the development of hypertension, which is known to be associated with changes in expression of vascular gap junction protein connexin 43 (Cx43). The aim of the study was to examine the distribution and expression of Cx43 in the aortic endothelium of adult normotensive Wistar rats (W), borderline hypertensive rats (BHR) and spontaneously hypertensive rats (SHR). Rings of the thoracic aorta were processed for immunofluorescence and Western blot analysis of endothelial Cx43 and for electron microscopy. Both, BHR and SHR exhibited significantly increased blood pressure vs. W (132+/-2 mm Hg and 185+/-3 mm Hg vs. 110+/-2 mm Hg). Reduced Cx43 immunofluorescence was observed in the endothelium of BHR and these alterations were more pronounced in SHR. Western blot analysis showed significant suppression of Cx43 expression in the aorta of both BHR (p<0.05) and SHR (p<0.001) vs. W. Electron microscopy revealed local subcellular alterations of interendothelial connections in BHR including extended tight junctions. These alterations were more frequent and marked in SHR. The results indicate that connexin 43 expression is reduced in the aortic endothelium already in prehypertensive period, which may affect cell-to-cell communication and thus participate in acceleration of hypertensive disease.
- MeSH
- Aorta, Thoracic chemistry ultrastructure MeSH
- Endothelium, Vascular chemistry ultrastructure MeSH
- Down-Regulation MeSH
- Fluorescent Antibody Technique MeSH
- Hypertension metabolism pathology physiopathology MeSH
- Connexin 43 analysis MeSH
- Blood Pressure MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Rats, Inbred SHR MeSH
- Rats, Wistar MeSH
- Disease Progression MeSH
- Tight Junctions chemistry MeSH
- Microscopy, Electron, Transmission MeSH
- Blotting, Western MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- MeSH
- Microscopy, Electron methods utilization MeSH
- Research Support as Topic MeSH
- Fluorescent Antibody Technique methods utilization MeSH
- Connexin 43 analysis MeSH
- Rats MeSH
- Seminiferous Epithelium anatomy & histology cytology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Meeting Abstract MeSH
We hypothesized that hypertension-related myocardial remodeling characterized by hypertrophy and fibrosis might be accompanied by cell-to-cell gap junction alterations that may account for increased arrhythmogenesis. Intercellular junctions and expression of gap junction protein connexin-43 were analyzed in rat heart tissues from both spontaneous (SHR) and L-NAME model of hypertension. Isolated heart preparation was used to examine susceptibility of the heart to lethal ventricular fibrillation induced by low potassium perfusion. Ultrastructure observation revealed enhanced neoformation of side-to-side type while internalization of end-to-end type (intercalated disc-related) of gap junctions prevailed in the myocardium of rats suffering from either spontaneous or L-NAME-induced hypertension. In parallel, immunolabeling showed increased number of connexin-43 positive gap junctions in lateral cell membrane surfaces, particularly in SHR. Besides, focal loss of immunopositive signal was observed more frequently in hearts of rats treated with L-NAME. There was a significantly higher incidence of hypokalemia-induced ventricular fibrillation in hypertensive compared to normotensive rat hearts. We conclude that adaptation of the heart to hypertension-induced mechanical overload results in maladaptive gap junction remodeling that consequently promotes development of fatal arrhythmias.
- MeSH
- Potassium MeSH
- Ventricular Fibrillation chemically induced metabolism MeSH
- Adaptation, Physiological MeSH
- Hypertension metabolism pathology MeSH
- Hypokalemia metabolism MeSH
- Connexin 43 metabolism MeSH
- Rats MeSH
- Gap Junctions metabolism MeSH
- Myocardium metabolism ultrastructure MeSH
- Rats, Inbred SHR MeSH
- Rats, Wistar MeSH
- Heart Ventricles microbiology virology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
Our and other studies suggest that myocardial hypertrophy in response to hypertension and hyperthyroidism increases propensity of the heart to malignant arrhythmias, while these are rare in conditions of hypothyroidism or type-1 diabetes mellitus associated with myocardial atrophy. One of the crucial factors impacting the susceptibility of the heart to life-threatening arrhythmias is gap junction channel protein connexin-43 (Cx43), which ensure cell-to-cell coupling for electrical signal propagation. Therefore, we aimed to explore Cx43 protein abundance and its topology in hypertrophic and hypotrophic cardiac phenotype. Analysis were performed in left ventricular tissue of adult male spontaneously hypertensive rat (SHR), Wistar Kyoto rats treated for 8-weeks with L-thyroxine, methimazol or strepotozotocin to induce hyperthyroid, hypothyroid and type-1 diabetic status as well as non-treated animals. Results showed that comparing to healthy rats there was a decrease of total myocardial Cx43 and its variant phosphorylated at serine368 in SHR and hyperthyroid rats. Besides, enhanced localization of Cx43 was demonstrated on lateral sides of hypertrophied cardiomyocytes. In contrast, total Cx43 protein and its serine368 variant were increased in atrophied left ventricle of hypothyroid and type-1 diabetic rats. It was associated with less pronounced alterations in Cx43 topology. In parallel, the abundance of PKCepsilon, which phosphorylates Cx43 at serine368 that stabilize Cx43 function and distribution was reduced in hypertrophied heart while enhanced in atrophied once. Findings suggest that differences in the abundance of cardiac Cx43, its variant phosphorylated at serine368 and Cx43 topology may explain, in part, distinct propensity of hypertrophied and atrophied heart to malignant arrhythmias.
- MeSH
- Atrophy pathology MeSH
- Diabetes Mellitus, Type 1 * metabolism MeSH
- Diabetes Mellitus, Experimental * metabolism MeSH
- Hypertrophy metabolism MeSH
- Hyperthyroidism * complications metabolism MeSH
- Hypothyroidism * metabolism MeSH
- Connexin 43 metabolism MeSH
- Connexins MeSH
- Rats MeSH
- Myocardium metabolism MeSH
- Pilot Projects MeSH
- Rats, Inbred SHR MeSH
- Rats, Inbred WKY MeSH
- Arrhythmias, Cardiac pathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
We have examined the changes of intercellular electrical coupling protein connexin-43 (Cx43) and of PKC-epsilon in heart atria of diabetic rats and/or after the treatment with triiodothyronine (T(3)). Diabetes was induced in Wistar-Kyoto rats by streptozotocin (50 mg/kg, i.v.) and atria were examined after 5 (acute stage) and 10 (chronic stage) weeks. T(3) (10 microg/100 g/day) was applied via a gastric tube for the last 10 days prior to the end of the experiments to non-diabetic and to the half of diabetic rats. Expression and phosphorylated status of Cx43, as well as expression of PKC-epsilon, were analyzed by Western blots using mouse monoclonal anti-Cx43 and rabbit polyclonal anti-PKC-epsilon antibodies. We found that the Cx43 expression was significantly increased after the treatment with T(3) and in the acute diabetes. Both in diabetes and after T(3) treatment the phosphorylation of Cx43 isoforms was markedly suppressed compared to the non-diabetic and T(3)-untreated controls. Such a down-regulation was less pronounced in diabetic rats after the T(3)-treatment. The expression of atrial PKC-epsilon was increased in diabetic rats. This increase was suppressed after T(3) administration and the expression was decreased in T(3)-treated non-diabetic rats. We suggest that the reduced Cx43 phosphorylation in diabetic and hyperthyroid rats can deteriorate a cell-to-cell coupling and consequently facilitate a development of atrial tachyarrhythmia in diabetic or hyperthyroid animals.
- MeSH
- Diabetes Mellitus, Experimental complications metabolism MeSH
- Atrial Fibrillation complications metabolism MeSH
- Financing, Organized MeSH
- Phosphorylation MeSH
- Hyperthyroidism chemically induced complications metabolism MeSH
- Connexin 43 metabolism MeSH
- Blood Glucose metabolism MeSH
- Rats MeSH
- Myocardium metabolism MeSH
- Rats, Inbred WKY MeSH
- Protein Kinase C-epsilon metabolism MeSH
- Heart Atria metabolism MeSH
- Tachycardia, Supraventricular complications metabolism MeSH
- Triiodothyronine pharmacology MeSH
- Up-Regulation physiology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
