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  • Title: Pacing-induced cardiac gap junction remodeling: modulation of connexin43 phosphorylation state.
    Author: Matsushita S, Tran VN, Pelleg A, Wechsler AS, Kresh JY.
    Journal: Am J Ther; 2009; 16(3):224-30. PubMed ID: 19454861.
    Abstract:
    BACKGROUND: Altered myocardial distribution of gap junctions and intercellular coupling have been implicated in nonuniform conduction of the depolarization wave and repolarization asynchrony in the mammalian heart. We tested the hypothesis that short-term cardiac pacing is associated with structural remodeling of gap junctions and their altered spatial distribution in cardiac myocytes in the immediate vicinity of the pacing site. MATERIALS AND METHODS: Isolated adult male rat hearts (n = 8) were perfused using a Langendorff apparatus. A multimicroelectrode array pacing catheter was positioned in the endocardial apical region of the right ventricle. Pacing (330 bpm; stimulus: 1.5 V, 5 milliseconds) was applied for 3 hours. Immunoblotting and immunohistochemical assays [using serine specific (Ser368) anti-connexin43 and anti-phosphoserine antibody] were used to determine the phosphorylation state of connexin43 (Cx43) and to determine its spatial distribution. RESULTS: Pacing was associated with a consistent, increased dephosphorylation state of Cx43 at the pacing site when compared to remote regions. In control hearts, Cx43 manifested a predominantly phosphorylated state; Western blotting analysis showed that dephosphorylated Cx43 was more abundant (1.5 +/- 0.33-fold) in the paced hearts than in controls (P < 0.02). Global cardiac function parameters, such as developed left ventricular pressure and oxygen demand index (rate-pressure product), did not differ significantly in paced hearts compared with controls (P > 0.05). CONCLUSIONS: A relatively short period of cardiac asynchronous pacing is associated with remodeling of gap junctions as manifested in the altered phosphorylation state of their constituent Cx43. This effect is confined to the myocardial tissue surrounding the pacing electrodes and does not alter global cardiac mechanics and energetics. These results, considered together with the known involvement of Ser368 in the gating of Cx43 and the putative role of Cx43 in the intercellular conductance, suggest that pacing-induced localized gap junctional remodeling could contribute to the creation of a reentrant substrate.
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