Thyroid hormones suppress epsilon-PKC signalling, down-regulate connexin-43 and increase lethal arrhythmia susceptibility in non-diabetic and diabetic rat hearts.
We examined whether thyroid hormones affect myocardial epsilon-PKC signalling, downstream target substrate, connexin-43 (Cx43) and arrhythmogenesis in non-diabetic and diabetic rats. Diabetes was induced by a single streptozotocin injection (50mg/kg, i.v.). Triiodothyronine (T(3)) was applied by gavage (1microg/kg of body weight for 10 days) to 4 weeks and 9 weeks diabetic and age-matched non-diabetic rats. Western blot analysis of Cx43 and epsilon-PKC, immunofluorescence of Cx43, ultrastructure of cardiomyocytes and myocardial conduction velocity were performed. Isolated perfused heart preparation was used to test ventricular fibrillation susceptibility. T(3) significantly decreased epsilon-PKC expression in non-diabetic and suppressed in diabetic rat heart ventricles. Decline of epsilon-PKC signalling was associated with decrease of Cx43 phosphorylation in diabetic and to a greater extent in non-diabetic rat hearts. However, conduction velocity was significantly decreased in diabetic while enhanced due to T(3) and increased in non-diabetic T(3)-treated rat heart ventricles compared to non-treated. T(3)-induced down-regulation of Cx43 was associated with increased cardiac propensity to ventricular fibrillation. Findings indicate that activation of epsilon-PKC signalling linked with phosphorylation of Cx43 is one of the mechanisms involved in the adaptation of the heart to hyperglycemia. Suppression of epsilon-PKC and Cx43 phosphorylation by T(3) abolish benefit of adaptation rendering the heart prone to lethal arrhythmias.
Lin
H
H
Department of Physiology, Fukuoka University Medical School, Fukuoka, Japan.
Mitasikova
M
M
Dlugosova
K
K
Okruhlicova
L
L
Imanaga
I
I
Ogawa
K
K
Weismann
P
P
Tribulova
N
N
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D018031:Connexin 43 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D004198:Disease Susceptibility; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013963:Thyroid Hormones / Q000494:pharmacology*
D018031:Connexin 43; D013963:Thyroid Hormones; D051744:Protein Kinase C-epsilon