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YIA5 Plakoglobin Deficiency Leads to Increased Biventricular Beta-Catenin Expression in the Murine Heart
  1. Jason Kei Chak Mak1,
  2. Fahima Syeda1,
  3. Ting Yue Yu1,
  4. Eleni Vloumidi1,
  5. Katja Gehmlich2,
  6. Larissa Fabritz1,
  7. Paulus Kirchhof1
  1. 1University of Birmingham, Centre of Cardiovascular Sciences, School of Clinical and Experimental Medicine
  2. 2University of Oxford, Department of Cardiovascular Medicine, Radcliffe Department of Medicine

Abstract

Introduction Cell-cell contact proteins including plakoglobin (γ-catenin, plako) play a critical role in the pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Development of the ARVC phenotype has been shown to be accelerated by endurance training. In swim-trained heterozygous plako-deficient (plako+/-) mice with an ARVC phenotype comprised of arrhythmias and right ventricular dilation, expression of the gap junction protein connexin43 (Cx43) was found to be pronouncedly decreased. This was associated with functional conduction block and a reduction in longitudinal conduction velocities. However, it is unclear if junctional protein changes other than plako deficiency itself exist prior to ARVC disease onset in plako deficiency.

Purpose To investigate the specific expression of plako, β-catenin (a structural homologue of plako), and Cx43 in left and right ventricles (LV and RV) from young sedentary asymptomatic plako+/- mice.

Methods Echocardiography was performed on anaesthetised 19-week-old littermate plako+/- and wildtype (WT) mice (n = 21–22). Freshly-prepared LV and RV samples (5 per genotype for each ventricle) were snap-frozen and protein expression quantitatively assessed using SDS-PAGE/Western blotting. All experiments were blinded to genotype.

Results ARVC phenotype was not apparent at this stage, as reflected by normal RV size (e.g. diastolic diameter: plako+/- 1.60 ± 0.03 mm vs WT 1.65 ± 0.03 mm). Plako expression was decreased in plako+/- hearts compared to WT for both LV (plako+/- 0.06 ± 0.01 vs WT 0.08 ± 0.01; p < 0.05) and RV (plako+/- 0.61 ± 0.04 vs WT 0.95 ± 0.07; p < 0.01), consistent with the heterozygous plako deficiency. In contrast, increased β-catenin expression was found in both plako+/- LV (plako+/- 0.11 ± 0.01 vs WT 0.07 ± 0.01; p < 0.01) and RV (plako+/- 0.22 ± 0.02 vs WT 0.13 ± 0.01; p < 0.01). Neither total (LV plako+/- 0.24 ± 0.03 vs WT 0.27 ± 0.04; RV plako+/- 0.82 ± 0.11 vs WT 0.77 ± 0.16) nor non-phosphorylated Cx43 levels (LV plako+/- 0.50 ± 0.05 vs WT 0.55 ± 0.07; RV plako+/- 0.09 ± 0.02 vs WT 0.14 ± 0.02) were found to be significantly down-regulated in the plako+/- group. [Figure shows RV plako and β-catenin expression normalised to the loading control calnexin, as well as representative blots.]

Abstract YIA5 Figure 1

Decreased plakoglobin and increased β​-catenin expression in the right ventricle of young sedentary asymptomatic plakoglobin heterozygous deficient (plako+/-) mice compared to wildtype (n = 5 per genotype). Representative blot shown with calnexin loading control

Conclusions β-catenin expression is increased in LV and RV of young sedentary plako+/- mice with confirmed deficiency of plako protein expression. This may reflect a compensatory response to the reduced levels of plako. Our results suggest that Cx43 expression is not critically down-regulated prior to ARVC disease onset.

  • plakoglobin
  • β-catenin
  • sedentary

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