摘要:

At the border zone of myocardial infarcts, surviving cardiomyocytes achieve drastic remodeling of cell-cell and cell–extracellular matrix interactions. Spatiotemporal changes in these interactions are likely related to each other and possibly have significant impact on cardiac function. To elucidate the changes, we conducted experimental infarction in rats and performed 3-dimensional analysis of the localization of gap junctions (connexin43), desmosomes (desmoplakin), adherens junctions (cadherin), and integrins (&bgr;1-integrin) by immunoconfocal microscopy. After myocardial infarction, changes in the distribution of gap junctions, desmosomes, and adherens junctions showed a similar but nonidentical tendency. In the early phase, gap junctions almost disappeared at stumps (longitudinal edges of cardiomyocytes facing the infarct), and, although desmosomes and adherens junctions decreased, they still remained. In the healing phase, at stumps, connexin43, desmoplakin, and cadherin were closely associated between multiple cell processes originating from a single cardiomyocyte. Electron microscopy confirmed the presence of junctional complexes between the cell processes. &bgr;1-Integrin at the cell process increased during the formation of papillary myotendinous junction–like structures. Abnormal localization of connexin43 was often accompanied by desmoplakin and cadherin on lateral surfaces of surviving cardiomyocytes. These findings suggested that remodeling of gap junction distribution was closely linked to changes in desmosomes and adherens junctions and that temporary formation of intracellular junctional complexes was an element of the remodeling of cell-cell and cell–extracellular matrix interactions after myocardial infarction. Moreover, the remodeling of the intercalated disk region at the myocardial interface with area of scar tissues was associated with the acquisition of extracellular matrix and &bgr;1-integrin.

ISSN:0009-7330    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Mechanisms of defibrillation remain poorly understood. Defibrillation success depends on the elimination of fibrillation without shock-induced arrhythmogenesis. We optically mapped selected epicardial regions of rabbit hearts (n=20) during shocks applied with the use of implantable defibrillator electrodes during the refractory period. Monophasic shocks resulted in virtual electrode polarization (VEP). Positive values of VEP resulted in a prolongation of the action potential duration, whereas negative polarization shortened the action potential duration, resulting in partial or complete recovery of the excitability. After a shock, new propagated wavefronts emerged at the boundary between the 2 regions and reexcited negatively polarized regions. Conduction velocity and maximum action potential upstroke rate of rise dV/dtmaxof shock-induced activation depended on the transmembrane potential at the end of the shock. Linear regression analysis showed that dV/dtmaxof postshock activation reached 50% of that of normal action potential at aVmvalue of −56.7±0.6 mV postshock voltage (n=9257). Less negative potentials resulted in slow conduction and blocks, whereas more negative potentials resulted in faster conduction. Although wavebreaks were produced in either condition, they degenerated into arrhythmias only when conduction was slow. Shock-induced VEP is essential in extinguishing fibrillation but can reinduce arrhythmias by producing excitable gaps. Reexcitation of these gaps through progressive increase in shock strength may provide the basis for the lower and upper limits of vulnerability. The former may correspond to the origination of slow wavefronts of reexcitation and phase singularities. The latter corresponds to fast conduction during which wavebreaks no longer produce sustained arrhythmias.

ISSN:0009-7330    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Action potential duration is prolonged in many forms of heart disease, often as a result of reductions in Ca2+-independent transient outward K+currents (ie,Ito). To examine the effects of a primary reduction inItocurrent in the heart, transgenic mice were generated that express a dominant-negative N-terminal fragment of the Kv4.2 pore-forming potassium channel subunit under the control of the mouse &agr;-myosin heavy chain promoter. Two of 6 founders died suddenly, and only 1 mouse successfully transmitted the transgene in mendelian fashion. Electrophysiological analysis at 2 to 4 weeks of age demonstrated thatItodensity was specifically reduced and action potential durations were prolonged in a subset of transgenic myocytes. The heterogeneous reduction inItowas accompanied by significant prolongation of monophasic action potentials. In vivo hemodynamic studies at this age revealed significant elevations in the mean arterial pressure, peak systolic ventricular pressures, and ±dP/dt, indicative of enhanced contractility. Surprisingly, by 10 to 12 weeks of age, transgenic mice developed clinical and hemodynamic evidence of congestive heart failure. Failing transgenic hearts displayed molecular and cellular remodeling, with evidence of hypertrophy, chamber dilatation, and interstitial fibrosis, and individual myocytes showed sharp reductions inItoandIK1densities, action potential duration prolongation, and increased cell capacitance. Our results confirm that Kv4.2 subunits contribute toItoin the mouse and demonstrate that manipulation of cardiac excitability may secondarily influence contractile performance.

ISSN:0009-7330    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Cardiac &bgr;2-adrenergic receptor (&bgr;2AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing &bgr;2ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of &bgr;2AR overexpression during ischemia, perfused hearts from TG4 and wild-type mice were subjected to 20-minute ischemia and 40-minute reperfusion. During ischemia, ATP and pH fell lower in TG4 hearts than wild type. Ischemic injury was greater in TG4 hearts, as indicated by lower postischemic recoveries of contractile function, ATP, and phosphocreatine. Because &bgr;2ARs, unlike &bgr;1ARs, couple to Gias well as Gs, we pretreated mice with the Giinhibitor pertussis toxin (PTX). PTX treatment increased basal contractility in TG4 hearts and abolished the contractile resistance to isoproterenol. During ischemia, ATP fell lower in TG4+PTX than in TG4 hearts. Recoveries of contractile function and ATP were lower in TG4+PTX than in TG4 hearts. We also studied mice that overexpressed either &bgr;ARK1 (TG&bgr;ARK1) or a &bgr;ARK1 inhibitor (TG&bgr;ARKct). Recoveries of function, ATP, and phosphocreatine were higher in TG&bgr;ARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TG&bgr;ARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, &bgr;2AR overexpression increased ischemic injury, whereas &bgr;ARK1 overexpression was protective. Ischemic injury in the &bgr;2AR overexpressors was exacerbated by PTX treatment, implying that it was Gsnot Giactivity that enhanced injury. Unlike &bgr;2AR overexpression, basal contractility was increased by &bgr;ARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.

ISSN:0009-7330    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

We recently showed that the transient expression of a hemagglutinin (HA) epitope–tagged, constitutively active mutant of the G protein &agr;qsubunit (HA&agr;q*) in the hearts of transgenic mice is sufficient to induce cardiac hypertrophy and dilatation that continue to progress after HA&agr;q* protein becomes undetectable. We demonstrated that the activity of phospholipase C&bgr;, the immediate downstream target of activated G&agr;q, is increased at 2 weeks, when HA&agr;q* is expressed, but also at 10 weeks, when HA&agr;q* is no longer detectable. This observation suggested that the transient HA&agr;q* expression causes multiple, persistent changes in cellular signaling pathways. We now demonstrate changes in the level, activity, or both of several signaling components, including changes in the amount and hormone responsiveness of phospholipase C&bgr; enzymes, in the basal level of diacylglycerol (which predominantly reflects activation of phospholipase D), in the amount or distribution of protein kinase C (PKC) isoforms (PKC&agr;, PKC&dgr;, and PKC&egr;), and in the amount of several endogenous G proteins. These changes vary depending on the isoform of the signaling molecule, the chamber in which it is expressed, and the presence or absence of HA&agr;q*. Our results suggest that a network of linked signaling functions determines the development of hypertrophy. They also suggest that atria and ventricles represent different signaling domains. It is likely that such changes occur in other model systems in which the activity of a single signaling component is increased, either due to an activating mutation or due to overexpression of the wild type.

ISSN:0009-7330    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Recent studies have added complexities to the conceptual framework of cardiac &bgr;-adrenergic receptor (&bgr;-AR) signal transduction. Whereas the classical linear Gs–adenylyl cyclase–cAMP–protein kinase A (PKA) signaling cascade has been corroborated for &bgr;1-AR stimulation, the &bgr;2-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to Gs, &bgr;2-AR couples to pertussis toxin–sensitive Giproteins, Gi2and Gi3. The coupling of &bgr;2-AR to Giproteins mediates, to a large extent, the differential actions of the &bgr;-AR subtypes on cardiac Ca2+handling, contractility, cAMP accumulation, and PKA-mediated protein phosphorylation. The extent of Gicoupling in ventricular myocytes appears to be the basis of the substantial species-to-species diversity in &bgr;2-AR–mediated cardiac responses. There is an apparent dissociation of &bgr;2-AR–induced augmentations of the intracellular Ca2+(Cai) transient and contractility from cAMP production and PKA-dependent cytoplasmic protein phosphorylation. This can be largely explained by Gi-dependent functional compartmentalization of the &bgr;2-AR–directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during &bgr;-AR subtype stimulation. Emerging evidence also points to distinctly different roles of these &bgr;-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of &bgr;-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of &bgr;-AR subtypes in healthy and diseased hearts.

ISSN:0009-7330    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1999

数据来源: OVID