Molecular remodeling in atrial fibrillation: protective roles of small HSPs

PhD ceremony: Mr. L. Ke, 12.45 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Molecular remodeling in atrial fibrillation: protective roles of small HSPs

Promotor(s): prof. H.H. Kampinga, prof. R.H. Henning

Faculty: Medical Sciences

Atrial Fibrillation (AF), the most common sustained arrhythmia, is associated with substantial cardiovascular morbidity and mortality. AF has the tendency to become more persistent over time. Recently, an increased awareness of the role of “atrial remodeling” has advanced our understanding of the persistency of AF. The concept “atrial remodeling” defines any changes in atrial function or structure that promote the development of atrial arrhythmia. It can be divided into two principal forms: electrical remodeling and structural remodeling. Both have their specific molecular basis and are also termed as molecular remodeling. With the onset of tachycardia, the rapid and irregular atrial firing substantially causes abnormal electrophysiological properties like Ca²⁺ overload and subsequent reduction of Ca²⁺ transients (electrical remodeling). If this progresses, myolysis will occur that hallmarks the initiation of structural remodeling. Myolysis is characterized by degradation of the myofibril structure and leads to contractile dysfunction. In this thesis, we first provide evidence for a major role of calpain in the degradation of troponins (a major group of myofibril proteins) and contractile dysfunction. Using a HL-1 cell model and a newly developed in vivo Drosophila model for AF, we next show that a general upregulation of so-called Heat Shock Proteins (HSP) can effectively inhibit AF-related remodeling. We identified HSPB1, a prominent member of the family of human small HSP, as required and sufficient for this protection and also find other family members (HSPB6, 7, 8) to display similar protective roles. T his thesis therefore provides strong basis for targeting these HSPBs in human AF.