Abstract 12404: Loss of Enigma Homolog Protein Results in Dilated Cardiomyopathy
Enigma subfamily proteins (Enigma, Enigma homolog protein and Cypher) of the PDZ-LIM domain protein family interact with α-actinin-2 at the Z-line, a highly ordered structure at the junction between neighboring sarcomeres. Among the Enigma subfamily, Cypher has been demonstrated to play a pivotal role in the structural integrity of Z-lines, whereas the role of Enigma homolog protein (ENH) in muscle remains largely unclear. We identified new splice isoforms for ENH in the mouse heart. Dilated cardiomyopathy, impaired cardiac contraction, widened Z-lines and cardiac fetal gene upregulation were observed in ENH-null mice. Mice with cardiac-specific ENH ablation developed a similar dilated cardiomyopathy. Like Cypher, ENH interacted with the Z-line protein Calsarcin-1. Moreover, biochemical studies showed that ENH, Calsarcin-1and Cypher short isoform were within the same protein complex at the Z-line. Cypher short isoform and Calsarcin-1 proteins are specifically and progressively downregulated in ENH-null hearts, which is consistent with the severity of cardiomyopathy. Increased loss of this protein complex resulted in enhanced dilation in response to pressure overload in ENH-null hearts. Several signaling pathways are not altered but integrin and dystrophin glycoprotein complex were upregulated in the ENH-null hearts in order to compensate for destalilization of the Z-lines in the ENH hearts. Taken together, our data suggest that loss of ENH leads to progressive loss of CypherS and Calsarcin resulting in the loss of Z-line structural integrity and consequent perturbation of the connection between adjacent sarcomeres and extracellular matrix. This leads to a loss of optimal force transmission and a significant decrease in fractional shortening and ultimately dilated cardiomyopathy.
- © 2010 by American Heart Association, Inc.