Protein kinase Cε mediates salutary effects on electrical coupling induced by ischemic preconditioning

Hund, Thomas J.; Lerner, Deborah; Yamada, Kathryn A.; Schuessler, Richard B.; Saffitz, Jeffrey E.

doi:10.1016/j.hrthm.2007.05.030

Cited by 51 publications

(49 citation statements)

References 51 publications

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“…The present results expand and highlight the previously reported complexity of gap junction regulation and its contribution to propagation of the cardiac impulse. Multiple factors regulate gap junction function, including calcium, pH, oxidative stress, protein kinases, ischemia, and hypoxia (6,19,28,51,52).…”

Section: Discussionmentioning

confidence: 99%

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Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Shimoni¹,

Emmett²,

Schmidt³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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The incidence of diabetes mellitus is increasing. Cardiac dysfunction often develops, resulting in diverse arrhythmias. These arise from ion channel remodeling or from altered speed and pattern of impulse propagation. Few studies have investigated impulse propagation in the diabetic heart. We previously showed a reduced conduction reserve in the diabetic heart, with associated changes in intercellular gap junctions. The present study investigated whether these effects are sex specific. Hearts from control and streptozotocin-diabetic male and female rats were used. Optical mapping was performed with the voltage-sensitive dye di-4-ANEPPS, using Langendorff-perfused hearts. Isolated ventricular cells and tissue sections were used for immunofluorescent labeling of the gap junction protein connexin43 (Cx43). The gap junction uncoupler heptanol (0.75 mM) or elevated K+ (9 mM, to reduce cell excitability) produced significantly greater slowing of propagation in diabetic males than females. In ovariectomized diabetic females, 9 mM K+ slowed conduction significantly more than in nonovariectomized females. The subcellular redistribution (lateralization) of the gap junction protein Cx43 was smaller in diabetic females. Pretreatment of diabetic males with the angiotensin-converting enzyme inhibitor quinapril reduced Cx43 lateralization and the effects of 9 mM K+ on propagation. In conclusion, the slowing of cardiac impulse propagation in type 1 diabetes is smaller in female rats, partly due to the presence of female sex hormones. This difference is (partly) mediated by sex differences in activation of the cardiac renin-angiotensin system.

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Section: Discussionmentioning

confidence: 99%

“…Cx43 is tightly regulated by multiple factors (15). Some of these, such as high glucose, PKC expression/activity, and oxidative stress, are implicated in diabetic pathology (19,24,50). Importantly, gap junction remodeling, which occurs with many cardiac pathologies (6,38), may be triggered by elevated angiotensin (12,22).…”

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confidence: 99%

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Shimoni¹,

Emmett²,

Schmidt³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…40 We studied Cx43 phosphorylation state by examining the ratio of higher-to lower-molecular-weight bands believed to represent phosphorylated and nonphosphorylated-Cx43 respectively, as well as with a Ser368-phosphorylated Cx43-specific antibody. However, in addition to this important site, there are other potentially significant phosphorylation sites on Cx43, 41 and we cannot be certain that similar changes would have occurred at other sites.The quantitative relationship between fibrosis and AF remains to be elucidated, as does the effect of the spatial distribution of fibrosis on atrial conduction and AFsusceptibility. The findings of this study relate to the substrate for AF maintenance and do not bear on other determinants of AF occurrence, such as neurohormonal tone and atrial ectopic activity.…”

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confidence: 96%

Changes in Connexin Expression and the Atrial Fibrillation Substrate in Congestive Heart Failure

Burstein

Comtois

Michael

et al. 2009

Circulation Research

182

158

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Key Words: atrial fibrillation Ⅲ heart failure Ⅲ fibrosis Ⅲ gap junction Ⅲ connexin C ongestive heart failure (CHF) predisposes to atrial fibrillation (AF), although the underlying mechanisms remain incompletely understood. 1 Ventricular tachypacing produces a clinically relevant animal model of CHF. 2 The atria of dogs with ventricular tachypacing-induced CHF are characterized by structural remodeling, conduction abnormalities and the ability to sustain AF. 3 Myocardial electric continuity is assured by gap junctions, cell-to-cell connections that maintain low-resistance intercellular coupling via specialized hemichannel subunit proteins called connexins. Connexin (Cx)43 and Cx40 are the principle atrial gap junctional subunits 4 ; abnormalities in their expression and localization are commonly observed in patients and experimental animals with AF. 5 Phosphorylation of Cx43 can regulate channel assembly, 6 degradation, 7 and conductance. 8 In the ventricles, CHF produces hypophosphorylation of Cx43 and redistribution to lateral cell membranes, associated with proarrhythmic conduction slowing. 9,10 Little is known, however, about connexin changes during CHF-related atrial remodeling and their role in AF maintenance. The present study was designed to assess the changes in atrial connexin expression caused by tachypacing-induced CHF in the dog.In initial experiments, we noted significant changes in connexin phosphorylation and sought to understand their role in AF. We previously noted that the cessation of ventricular tachypacing, which is followed by the reversal of CHF, dissociates atrial size and function changes from structural remodeling and AF sustainability. 11,12 Both structural (particularly tissue fibrosis) and connexin remodeling could contribute to CHF-associated AF. We therefore exploited CHF reversal to assess the reversibility of atrial connexin alterations and evaluate their contribution to CHF-related conduction disturbances and AF maintenance. MethodsAn expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. Animal ModelAnimal-handling procedures followed National Institutes of Health guidelines. Animals were prepared and studied as described previously. 11,12 Forty-nine mongrel dogs (18 to 34 kg) were instrumented with a right ventricular tachypacemaker. Dogs were assigned to 3 groups: (1) pacemaker inactive sham controls (CTL group, nϭ19); (2) 2-week ventricular tachypacing at 240 bpm to induce CHF (CHF group, nϭ15); (3) 2-week ventricular tachypacing followed by 4-week recovery (REC group, nϭ16). Atrial effective refractory period (ERP) was measured with 10 basic (S1) stimuli. ERP was measured at multiple basic cycle lengths (BCLs) in the left atrial (LA) appendage of all dogs and at 7 additional sites (BCL, 300 ms) in 5 dogs per group. AF was induced by burst pacing and mean AF duration estimated based on 10 inductions. AF Ն30 minutes was considered sustained and was cardioverted. Five plastic arrays containing a total of 240 bipolar elect...

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“…Although several isozymes of protein kinase C (PKC) phosphorylate connexin-43 in diverse cell types and tissues, PKC is the only isoform that phosphorylates it at the ID (Bowling et al, 2001;Doble et al, 2000;Lampe et al, 2000;Lin et al, 2003;Saez et al, 1997). Consistent with this, PKC suppresses gap junction communication in the ischemic heart through phosphorylation of connexin-43 at Ser-368 (Ek-Vitorin et al, 2006;Hund et al, 2007;Hund et al, 2008). Several phosphorylation sites (i.e.…”

Section: Phosphorylation Regulates the Permeability Of Connexonsmentioning

confidence: 85%

Intercellular Connections in the Heart: The Intercalated Disc

Ackermann¹,

Hu²,

Kontrogianni‐Konstantopoulos³

2012

Cardiomyopathies - From Basic Research to Clinical Management

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Protein kinase Cε mediates salutary effects on electrical coupling induced by ischemic preconditioning

Abstract: Background-Ischemic preconditioning delays the onset of electrical uncoupling and prevents loss of the primary ventricular gap junction protein connexin43 (Cx43) from gap junctions during subsequent ischemia.

Cited by 51 publications

References 51 publications

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Changes in Connexin Expression and the Atrial Fibrillation Substrate in Congestive Heart Failure

Intercellular Connections in the Heart: The Intercalated Disc

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