Regulation of cardiomyocyte cohesion and arrhythmogenic cardiomyopathy

Current Lab Members:
Sunil Yeruva and Jens Waschke (Group leaders)
Konstanze Stangner (Postdoctoral fellow)
Maria Shoyket (PhD Student)
Anna Jungwirth (MD Student)
Lars Körber (MD student)
Kilian Skowranek (Technician)

Former Lab Members:
Camilla Schinner (MD Student)
Bernd Erber (MD Student)
Angela Wölfel (Postdoctoral fellow)
Silvana Olivares-Baerwald (Postdoctoral fellow)
Deepika Pothiraju (Postdoctoral fellow)
Ellen Kempf (MD student)
Sebastian Trentz (MD Student)

 

The myocardium predominantly consists of cardiomyocytes which require strong coupling to maintain heart function. Adjacent cardiomyocytes are coupled via intercalated disks (ICD) consisting of desmosomes, adherens junctions (AJ), and gap junctions, which together allow mechanical stability and electrical conduction of the heart muscle (Figure 1). Desmosomes, together with adherens junctions, provide cardiomyocyte cohesive strength necessary for strong mechanical coupling. They consist of the transmembrane adhesion molecules Dsg2 and desmocollin 2 (Dsc2), which are linked to the desmin intermediate filament system via the plaque proteins Pg, plakophilin 2 (Pkp2) and desmoplakin (DP) (Figure 1). Mutations affecting the desmosomal components of the ICD can cause Arrhythmogenic cardiomyopathy (AC), at least in part because they modulate the functions of the gap junctions composed of connexin 43.

 

Figure 1: Intercalated disc with desmosomal proteins (desmoglein 2, desmocollin 2), adherens junction protein (N-cadherin) and gap junction protein (Connexin 43)

Therefore, we are interested in investigating the mechanisms by which cardiomyocyte cohesion is regulated under pathophysiological conditions, with a major focus on finding the therapeutic targets for arrhythmogenic cardiomyopathy.
Our major findings as illustrated in figure 2 are that Adrenergic signaling (F/R and Iso), PKC activation (PMA), and p38MAPK inhibition (SB20) enhances basal cardiomyocyte cohesion, which we referred to as positive adhesiotropy, in an ERK1/2-dependent manner. Positive adhesiotropy is possibly achieved through alterations in the interactions of the desmosomal proteins PG, PKP2, and DP (represented by a dashed rectangle) that eventually lead to increased DSG2 translocation to the cell borders (represented by the dashed arrow) and finally to positive adhesiotropy (Shoyket et al., JCI Insight 2020). On the other hand, adrenergic signaling also acts via PKA-dependent PG phosphorylation at S665 (Schinner et al., Circ res 2017), leading to an ultrastructural strengthening of intercalated discs and thereby increases basal cardiomyocyte cohesion (Yeruva er al., Front Physiol 2020). In addition to the above mechanisms, we have also studied the role of ionotropic agent digitoxin on cardiomyocyte adhesion and observed that digitoxin induces recruitment of desmosomal proteins with the strengthening of the mechanical coupling of the ICD via ERK1/2 activation (Schinner et al., Basic Res. Cardiol. 2020).
As it is now accepted that desmosomal and AJ components are required for maintenance of electrical coupling of cardiomyocytes because multiple studies demonstrated the impairment of GJ function and distribution by the disrupted mechanical strength of the ICD. Therefore improvement of cardiomyocyte cohesion may be effective to rescue impaired electrical conduction. As we already proved in the pemphigus field that a peptide-based stabilization of intercellular cohesion was shown to be protective where autoantibodies against Dsg3 impair keratinocyte cohesion with induction of skin blistering. Thus, an analog approach could serve as a novel therapeutic target for treating arrhythmias in AC. To explore this avenue we studied whether a Dsg2-linking peptide (Dsg2-LP) could rescue the arrhythmias. We demonstrated for the first time that stabilization of Dsg2-mediated binding by a specific linking peptide is capable of rescuing both cardiomyocyte cohesion and GJ-mediated signal transduction caused by disruption of intercellular adhesion. Because arrhythmia in perfused hearts derived from an AC mouse model was successfully reduced by Dsg2-LP treatment, these results indicate that stabilization of Dsg2 binding can be an effective approach to treat AC (Schinner et al., JCI Insight 2020).

Figure 2: Signaling mechanisms regulating cardiomyocyte cohesion.

 

Publications

1. Shoykhet M, Trenz S, Kempf E, Williams T, Gerull B, Schinner C, Yeruva S, Waschke J. Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin. JCI Insight. 2020 Sep 17;5(18):e140066. doi: 10.1172/jci.insight.140066. PMID: 32841221
2. Schinner C, Olivares-Florez S, Schlipp A, Trenz S, Feinendegen M, Flaswinkel H, Kempf E, Egu DT, Yeruva S, Waschke J. The inotropic agent digitoxin strengthens desmosomal adhesion in cardiac myocytes in an ERK1/2-dependent manner. Basic Res Cardiol. 2020 Jun 17;115(4):46. doi: 10.1007/s00395-020-0805-3. PMID: 32556797
3. Yeruva S, Kempf E, Egu DT, Flaswinkel H, Kugelmann D, Waschke J. Adrenergic Signaling-Induced Ultrastructural Strengthening of Intercalated Discs via Plakoglobin Is Crucial for Positive Adhesiotropy in Murine Cardiomyocytes. Front Physiol. 2020 May 21;11:430. doi: 10.3389/fphys.2020.00430. eCollection 2020. PMID: 32508670.
4. Schinner C, Erber BM, Yeruva S, Schlipp A, Rötzer V, Kempf E, Kant S, Leube RE, Mueller TD, Waschke J. Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy JCI Insight. 2020 May 7;5(9):e130141. doi: 10.1172/jci.insight.130141. PMID: 32376797.
5. Schinner C, Erber BM, Yeruva S, Waschke J (2018) Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion. Acta Physiol (Oxf). Dec 23:e13242. Epub ahead of print. PMID: 30582290.
6. Schinner C, Vielmuth F, Rötzer V, Hiermaier M, Radeva MY, Co TK, Hartlieb E, Schmidt A, Imhof A, Messoudi A, Horn A, Schlipp A, Spindler V, Waschke J (2017) Adrenergic Signaling Strengthens Cardiac Myocyte Cohesion. Circ Res.120(8):1305-1317. PMID: 28289018.
7. Schlipp A, Schinner C, Spindler V, Vielmuth F, Gehmlich K, Syrris P, Mckenna WJ, Dendorfer A, Hartlieb E, Waschke J (2014) Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. Cardiovasc Res, 104(2):245-57. PMID: 25213555