An international team led by scientists from the National Centre for Cardiovascular Research (CNIC), in partnership with the University of Pavia and IRCCS Istituti Clinici Scientifici Maugeri in Italy, has discovered a protein degradation process involved in the development of a hereditary form of catecholaminergic polymorphic ventricular tachycardia (CPVT), a condition primarily affecting children and young adults.
The study, published in Circulation Research and involving the Network Center for Biomedical Research in Cardiovascular Diseases (CIBERCV), also highlights a potential therapeutic strategy based on inhibiting the enzyme calpain.
CPVT is an inherited arrhythmia disorder that can lead to life-threatening arrhythmias, loss of consciousness, and even sudden death, particularly in children and young adults. A dangerous characteristic of this disease is that arrhythmias frequently occur during exercise or emotional stress, when heart activity increases.
The research, led by Dr. Enrique Lara-Pezzi's group at CNIC and Dr. Silvia G. Priori from the University of Pavia, analyzed a form of CPVT caused by a mutation in the gene encoding calsequestrin, a protein that helps regulate calcium within heart cells. Calcium is essential for coordinated heart contractions, and its dysregulation can trigger abnormal heart rhythms.
Using a combination of proteomic techniques, experimental models, and cellular studies, the team found that the initial calcium handling anomaly activates cellular degradation mechanisms, reducing essential proteins in the calcium release machinery within cardiomyocytes. Calpain, a calcium-dependent enzyme, was identified as a key player, showing increased activity in mutated animals and degrading triadin (TRDN), a protein that stabilizes the calcium release machinery.
The findings reveal that triadin degradation precedes and contributes to the destabilization of the mutated calsequestrin. Pharmacological blockade of calpain in preclinical models successfully restored several proteins, improved cardiac cell calcium handling, and reduced ventricular arrhythmias in mice.
«Our results identify protein degradation as an important mechanism contributing to the development of this form of CPVT and show that calpain may represent a novel therapeutic target,» stated Dr. Laura Ramos-Hernández, the study's first author.
The authors emphasize that, as these are preclinical results, further research is needed to determine if this calpain-mediated degradation mechanism is present in other forms of CPVT and cardiac diseases, and to assess its potential translation to clinical practice.
The study was funded by the European Innovation Council (EIC) of the European Union, the Ministry of Science, Innovation and Universities, NextGenerationEU/PRTR, the European Research Council (ERC), and the Community of Madrid.
