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Clarke, Thomas Charles
Languages: English
Types: Doctoral thesis
Subjects: R1

Classified by OpenAIRE into

mesheuropmc: cardiovascular system, sense organs
In coronary heart disease, the blood supply to the myocardium is insufficient for its needs and leads to cardiac ischaemia, which is often accompanied by the onset of lethal cardiac arrhythmias. Electrical communication between cardiac myocytes occurs across gap junctions located in intercalated discs. Gap junctions are specialised structures of the plasma membrane which facilitate direct and rapid communication between adjacent cells. Connexin 43 (Cx43) is the most widely expressed of the connexin family and is the main connexin in the heart. A cardiac ischaemia model system was developed to study the various aspects of cardiac myocyte biology. Simulated ischaemia caused neonatal cardiac myocytes to cease synchronous contractions after 3-4 hours and was accompanied by the reversible dephosphorylation of Cx43 after 5 hours. Cx43 dephosphorylation was then reversed by reoxygenating the cells for 30 minutes. In hypoxia the myocytes continued to beat and Cx43 remained phosphorylated. Rotigaptide, an antiairhythmic peptide with protracted action, increased intercellular dye transfer in cardiac myocytes, atrial HL-1 cells and HeLa cells expressing Cx43. The communication-modifying effect of rotigaptide was confined to cells expressing Cx43 since the peptide had no effect on dye transfer in HeLa cells expressing Cx32 and Cx26. Rotigaptide had little effect on cell beating rate or Cx43 expression. Phosphorylation of Cx43 in normoxic and ischaemic cells was also unaffected. Simulated ischaemia induced cardiac myocytes to release a peak of ATP after 80 minutes that was blocked by the connexin mimetic peptide GAP 26 and the gap junction inhibitor 18-a glyccyrrhetinic acid. This suggested that the release of ATP occurred through connexin hemichannels (CxHcs). The rotigaptide analogue AAP10 increased the transient peak of ATP release caused by ischaemia. The model developed has provided a platform to study the effects of simulated ischaemia on Cx43 dependent functions in the heart. Rotigaptide and AAP10 emerge as novel peptides with therapeutic potential for treating heart arrhythmias.

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