New Cell Adhesion Molecules in Human Ischemic Cardiomyopathy. PCDHGA3 Implications in Decreased Stroke Volume and Ventricular Dysfunction

Autores de IIS La Fe

• Ana Ortega Gutierrez

  Autor

• Carolina Gil Cayuela

  Autor

• Estefanía Tarazón Melguizo

  Autor

• María Dolores García Manzanares

  Autor

• José Anastasio Montero Argudo

  Autor

• Manuel Portoles Sanz

  Autor

• Jose Miguel Rivera Otero

  Autor

• 

  Esther Roselló Lletí

  Autor

Participantes ajenos a IIS La Fe

• Cinca, Juan

Grupos

• Grupo de Investigación Clínica y Traslacional en Cardiología

• Regeneración y Trasplante Cardíaco

Abstract

Background Intercalated disks are unique structures in cardiac tissue, in which adherens junctions, desmosomes, and GAP junctions co-localize, thereby facilitating cardiac muscle contraction and function. Protocadherins are involved in these junctions; however, their role in heart physiology is poorly understood. We aimed to analyze the transcriptomic profile of adhesion molecules in patients with ischemic cardiomyopathy (ICM) and relate the changes uncovered with the hemodynamic alterations and functional depression observed in these patients. Methods and Results Twenty-three left ventricular tissue samples from patients diagnosed with ICM (n = 13) undergoing heart transplantation and control donors (CNT, n = 10) were analyzed using RNA sequencing. Forty-two cell adhesion genes involved in cellular junctions were differentially expressed in ICM myocardium. Notably, the levels of protocadherin PCDHGA3 were related with the stroke volume (r = -0.826, P = 0.003), ejection fraction (r = -0.793, P = 0.004) and left ventricular end systolic and diastolic diameters (r = 0.867, P = 0.001; r = 0.781, P = 0.005, respectively). Conclusions Our results support the importance of intercalated disks molecular alterations, closely involved in the contractile function, highlighting its crucial significance and showing gene expression changes not previously described. Specifically, altered PCDHGA3 gene expression was strongly associated with reduced stroke volume and ventricular dysfunction in ICM, suggesting a relevant role in hemodynamic perturbations and cardiac performance for this unexplored protocadherin.

Keywords

• HEART-FAILURE; EXTRACELLULAR-MATRIX; INTERCALATED DISKS; GENE-EXPRESSION; CONNEXIN43; PLAKOGLOBIN; GUIDELINES; MUTATIONS; DIVERSITY; JUNCTIONS