Basic Science and Experimental StudiesCardiac Contractility Modulation Electrical Signals Normalize Activity, Expression, and Phosphorylation of the Na+-Ca2+ Exchanger in Heart Failure
Section snippets
Materials
Dogs were purchased from Marshal Farms (North Rose, NY). Chemicals and supplies for electrophoresis and electrotransfer were purchased from Bio-Rad (Hercules, CA). Biochemical supplies were obtained from Sigma Chemical (St Louis, MO). Gene primers were synthesized by Operon Technologies, Inc (Alameda, CA). Primary antibodies for NCX-1 and calsequestrin (CSQ) were obtained from ABR, Inc (Golden, CO), and primary antibodies for Fog-2 and GATA-4 were obtained from Santa Cruz Biotechnologies, Inc
Results
The hemodynamic results obtained in all dogs included in this study have been reported.42 Briefly, in sham-operated HF control dogs, LV ejection fraction measured angiographically decreased from 27% ± 1% to 23% ± 1% during the 3 months of follow-up (P = .001). In contrast, LV ejection fraction increased from 27% ± 1% before initiating CCM therapy to 33% ± 1% after 3 months of CCM therapy (P = .0001).20
Discussion
CCM electrical signals delivered to the myocardium during the absolute refractory period have been shown to improve LV function both when delivered acutely and after long-term delivery in dogs with experimentally induced HF.4, 14, 40 In HF dogs, CCM therapy was associated with improved SR calcium cycling, as evidenced by increased activity and expression of calcium-ATPase and increased phosphorylation of phospholamban.40 CCM therapy in patients with chronic HF (New York Heart Association class
Conclusions
The results of the present study indicate that long-term therapy with CCM electric signals normalize the NCX-1, GATA-4, and FOG-2 signaling pathway in HF dogs. Normalization of components of this signaling pathway is consistent with and provides further support to previous observations of improved SR calcium cycling in HF dogs treated long-term with CCM electrical signals. These improvements in NCX-1 also represent a potential contributing factor to the improved LV function in HF.
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2016, European Journal of PharmacologyCitation Excerpt :Again, CamKII-dependent signaling is implicated in connecting the increased neurohormonal activation to the abnormal Ca2+-dependent regulation of cell function (Mollova et al., 2015). Accordingly, involvement of NCX upregulation and altered phosphorylation status play a key function in remodeling (Gupta et al., 2009; Katanosaka et al., 2007; Valdivia et al., 2015). Similar role of NCX in pathogenesis of atrial remodeling associated with atrial fibrillation has also been reported (see below).
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