Weary of the Stress

Abstract

See related article, pages 1233–1243 Heart failure affects more than 5 million people a year in the United States, and the underlying molecular causes are still poorly understood. Many studies have reported that pathways important for cardiac development are also important for adult cardiac homeostasis and response to injury and stress. In this issue of Circulation Research , Kim et al report the identification of a new Notch ligand, weary ( wry ), using an elegant genetic screen in Drosophila . wry is expressed in the Drosophila dorsal tube, the analog of the mammalian heart, and loss of wry results in dilated cardiomyopathy. The protein structure of wry suggests high similarity to known Notch ligands; however, it lacks the highly conserved Delta–Serrate–Lag domain found in other Notch ligands, suggesting divergence in both structure and function. Despite this difference, the authors show that wry can regulate Notch-mediated transcription in flies. These studies identify a new Notch ligand and show that this critical developmental pathway may be an important new target for future therapies directed toward adult cardiomyopathy. The adaptive response of the adult mammalian heart to various stressors and environmental insults is limited by its lack of regenerative potential. The result is often extensive cardiomyocyte hypertrophy, eventually followed by cardiomyocyte death, dilated myopathy, and heart failure. Although certain therapies can alleviate symptoms, there are no cures for heart failure outside of transplantation. Thus, new mechanistic insights into this important disease, as well as novel therapeutic targets, are essential for progress to occur. One of the standing paradigms in cardiac biology is that signaling and transcription pathways important for cardiac development are often reactivated in the hypertrophic response and subsequent heart failure. Much of the support for this argument comes from findings showing that embryonic isoforms of cardiac specific genes including myosin heavy …