Enhanced heterogeneity of myocardial conduction and severe cardiac electrical instability in annexin A7-deficient mice. Cardiovasc Res

University of Cologne, Köln, North Rhine-Westphalia, Germany
Cardiovascular Research (Impact Factor: 5.94). 11/2007; 76(2):257-68. DOI: 10.1016/j.cardiores.2007.07.001
Source: PubMed


Annexin A7 is involved in cardiomyocyte membrane organization and Ca(2+)-dependent signalling processes. We investigated the impact of annexin A7 on cardiac electrophysiological properties using an annexin A7-deficient mouse strain (annexin A7(-/-)).
Nineteen adult annexin A7(-/-) and 14 wild-type mice were examined electrophysiologically in vivo by transvenous catheterization. Hearts were additionally perfused by the Langendorff method and epicardial activation mapping was performed.
The susceptibility to induction of atrial fibrillation was elevated in annexin A7(-/-) mice. Ten deficient animals showed atrial fibrillation (AF) episodes > or =1 min and sustained AF > or =30 min was observed in 4 annexin A7(-/-) mice, but in none of the wild-type mice. The incidence of ventricular tachycardia (VT) was higher in annexin A7(-/-) mice and VT duration was prolonged. Epicardial mapping showed elevated anisotropy and inhomogeneity of conduction, leading to conduction blocks in the deficient mice. Besides alterations of intracellular calcium homeostasis, electron microscopy showed a homogeneous, electron-dense material that filled the myocardial intercellular compartments and accumulated at the basement membranes. This led to expansion of the extracellular spaces, which was the most probable substrate factor responsible for the disturbances of electrical communication.
Annexin A7 deficiency causes severe electrical instability in the murine heart, including conduction disturbances and anisotropy of impulse propagation, which is accompanied by disturbed calcium handling and intercellular deposits.

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Available from: Kathrin Reetz, Oct 08, 2015
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    • "Some loss-of-function mutants of annexin have impaired ability to regulate cytoplasmic Ca 2+ . These include, for example, A5 (2/2) chicken DT40 cells (Kubista et al. 1999), A7 (+/2) murine brain cells (Watson et al. 2004), and A7 (2/2) murine cardiomyocytes (Schrickel et al. 2007). In plants, a Zea mays annexin could increase [Ca 2+ ] cyt of Arabidopsis protoplasts when the recombinant annexin was added to the root protoplasts expressing the calcium sensor protein, aequorin (Demidchik et al. 2002; Dodd et al. 2006). "
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    ABSTRACT: Cotton fiber is a single cell that differentiates from the ovule epidermis and undergoes synchronous elongation with high secretion and growth rate. Apart from economic importance, cotton fiber provides an excellent single-celled model for studying mechanisms of cell-growth. Annexins are Ca2+- and phospholipid-binding proteins that have been reported to be localized in multiple cellular compartments and involved in control of vesicle secretions. Although several annexins have been found to be highly expressed in elongating cotton fibers, their functional roles in fiber development remain unknown. Here, 14 annexin family members were identified from the fully sequenced diploid G. raimondii (D5 genome), half of which were expressed in fibers of the cultivated tetraploid species G. hirsutum (cv. YZ1). Among them, GhAnn2 from the D genome of the tetraploid species displayed high expression level in elongating fiber. The expression of GhAnn2 could be induced by some phytohormones that play important roles in fiber elongation, such as IAA and GA3. RNAi-mediated down-regulation of GhAnn2 inhibited fiber elongation and secondary cell wall synthesis, resulting in shorter and thinner mature fibers in the transgenic plants. Measurement with non-invasive scanning ion-selective electrode revealed that the rate of Ca2+ influx from extracellular to intracellular was decreased at the fiber cell apex of GhAnn2 silencing lines, in comparison to that in the wild type. These results indicate that GhAnn2 may regulate fiber development through modulating Ca2+ fluxes and signaling.
    Plant Molecular Biology 06/2014; 85(6). DOI:10.1007/s11103-014-0208-7 · 4.26 Impact Factor
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    • "We extracted cardiomyocytes from hearts after 3 days I/R using Langendorff-apparatus (Radnoti Technologies Inc., Monrovia, CA, USA) in order to measure the cardiomyocyte specific mRNA-expression of osteopontin as previously described [14]. Briefly, ischemic hearts were perfused with collagenase B (Roche, Mannheim, Germany) for digestion. "
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    ABSTRACT: Repetitive brief ischemia and reperfusion (I/R) is associated with ventricular dysfunction in pathogenesis of murine ischemic cardiomyopathy and human hibernating myocardium. We investigated the role of matricellular protein osteopontin-1 (OPN) in murine model of repetitive I/R. One 15-min LAD-occlusion followed by reperfusion was performed daily over 3, 5, and 7 consecutive days in C57/Bl6 wildtype- (WT-) and OPN(-/-)-mice (n = 8/group). After echocardiography hearts were processed for histological and mRNA-studies. Cardiac fibroblasts were isolated, cultured, and stimulated with TGF- β 1. WT-mice showed an early, strong, and cardiomyocyte-specific osteopontin-expression leading to interstitial macrophage infiltration and consecutive fibrosis after 7 days I/R in absence of myocardial infarction. In contrast, OPN(-/-)-mice showed small, nontransmural infarctions after 3 days I/R associated with significantly worse ventricular dysfunction. OPN(-/-)-mice had different expression of myocardial contractile elements and antioxidative mediators and a lower expression of chemokines during I/R. OPN(-/-)-mice showed predominant collagen deposition in macrophage-rich small infarctions. We found lower induction of tenascin-C, MMP-9, MMP-12, and TIMP-1, whereas MMP-13-expression was higher in OPN(-/-)-mice. Cultured OPN(-/-)-myofibroblasts confirmed these findings. In conclusion, osteopontin seems to modulate expression of contractile elements, antioxidative mediators, and inflammatory response and subsequently remodel in order to protect cardiomyocytes in murine ischemic cardiomyopathy.
    BioMed Research International 05/2014; 2014:124063. DOI:10.1155/2014/124063 · 2.71 Impact Factor
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    • "Heart rate, P wave duration, QRS duration and QTc interval were measured by successive evaluation of 10 RR complexes in the most distinguishable tracings. Electrophysiological investigation with induction of arrhythmias was performed as described previously [37]. Intracardiac atrial and ventricular recording and atrial stimulation maneuvers were performed using a CardioTek EPTracer (Biotronik). "
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    ABSTRACT: Recent observational clinical and ex-vivo studies suggest that inflammation and in particular leukocyte activation predisposes to atrial fibrillation (AF). However, whether local binding and extravasation of leukocytes into atrial myocardium is an essential prerequisite for the initiation and propagation of AF remains elusive. Here we investigated the role of atrial CD11b/CD18 mediated infiltration of polymorphonuclear neutrophils (PMN) for the susceptibility to AF. C57bl/6J wildtype (WT) and CD11b/CD18 knock-out (CD11b(-/-)) mice were treated for 14 days with subcutaneous infusion of angiotensin II (Ang II), a known stimulus for PMN activation. Atria of Ang II-treated WT mice were characterized by increased PMN infiltration assessed in immunohistochemically stained sections. In contrast, atrial sections of CD11b(-/-) mice lacked a significant increase in PMN infiltration upon Ang II infusion. PMN infiltration was accompanied by profoundly enhanced atrial fibrosis in Ang II treated WT as compared to CD11b(-/-) mice. Upon in-vivo electrophysiological investigation, Ang II treatment significantly elevated the susceptibility for AF in WT mice if compared to vehicle treated animals given an increased number and increased duration of AF episodes. In contrast, animals deficient of CD11b/CD18 were entirely protected from AF induction. Likewise, epicardial activation mapping revealed decreased electrical conduction velocity in atria of Ang II treated WT mice, which was preserved in CD11b(-/-) mice. In addition, atrial PMN infiltration was enhanced in atrial appendage sections of patients with persistent AF as compared to patients without AF. The current data critically link CD11b-integrin mediated atrial PMN infiltration to the formation of fibrosis, which promotes the initiation and propagation of AF. These findings not only reveal a mechanistic role of leukocytes in AF but also point towards a potential novel avenue of treatment in AF.
    PLoS ONE 02/2014; 9(2):e89307. DOI:10.1371/journal.pone.0089307 · 3.23 Impact Factor
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