RESUMEN

RATIONALE: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current (I(to)) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I(to) and that its overexpression might specifically alter PF I(to) properties and repolarization. OBJECTIVE: To assess the potential role of DPP6 in PF I(to). METHODS AND RESULTS: Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and ventricular muscle I(to) had similar density, but PF I(to) differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I(to) density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K(+)-channel interacting ß-subunit K(+)-channel interacting protein type-2, essential for normal expression of I(to) in ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I(to); I(to) amplitude was greatly enhanced by coexpression with K(+)-channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K(+)-channel interacting protein type-2 failed to alter I(to) compared with Kv4.3/K(+)-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I(to) composition) greatly enhanced I(to) compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I(to) enhancement can greatly accelerate PF repolarization. CONCLUSIONS: These results point to a previously unknown central role of DPP6 in PF I(to), with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation.

Asunto(s)

Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/fisiología , Proteínas de Interacción con los Canales Kv/fisiología , Proteínas del Tejido Nervioso/fisiología , Canales de Potasio/fisiología , Ramos Subendocárdicos/fisiología , Canales de Potasio Shal/fisiología , Fibrilación Ventricular/fisiopatología , Adulto , Animales , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Modelos Animales de Enfermedad , Perros , Femenino , Técnicas de Silenciamiento del Gen , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Técnicas In Vitro , Proteínas de Interacción con los Canales Kv/efectos de los fármacos , Proteínas de Interacción con los Canales Kv/genética , Masculino , Persona de Mediana Edad , Modelos Teóricos , Proteínas del Tejido Nervioso/genética , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/efectos de los fármacos , Canales de Potasio/genética , Ramos Subendocárdicos/patología , Canales de Potasio Shal/efectos de los fármacos , Canales de Potasio Shal/genética , Tetraetilamonio/farmacología , Transfección