Heart Making and Heart Breaking: The Molecular Circuitry of Heart Development, Disease and Regeneration
Heart disease remains the primary cause of morbidity and mortality in the developed world. A major reason for this is that the adult human heart has limited regenerative capacity following injury. The default healing response in the adult heart following myocardial infarction or other disorders that cause loss of heart muscle cells involves replacement of cardiac muscle with fibrous, noncontractile scar tissue. The consequent loss of contractility diminishes cardiac function and ultimately leads to heart failure and death. In recent studies, we found that the hearts of neonatal mice can fully regenerate after partial surgical resection, but this capacity is lost by 7 days of age. We are currently exploring the molecular underpinnings of the neonatal regenerative response of the heart, with the long-term goal of discovering combinations of genes and drugs that promote cardiac repair and regeneration. We are also optimizing strategies for reprogramming of cardiac fibroblasts toward a cardiomyocyte cell fate as a means of replacing heart muscle following myocardial infarction. It has recently become apparent that microRNAs play key roles in modulating the response of the heart to injury. Because individual microRNAs often regulate the expression of multiple target genes with related functions, modulating the expression of a single microRNA can modify complex disease phenotypes. We have identified signature expression patterns of microRNAs associated with diverse cardiovascular disorders, including pathological cardiac hypertrophy, heart failure, myocardial infarction, vascular stenosis and angiogenesis. Gain- and loss-of-function studies in mice have revealed striking functions for these microRNAs in numerous facets of cardiac biology, including the control of sarcomere formation, fibrosis, hypoxia, myocyte survival, cytoskeletal dynamics and erythropoiesis. Disease-inducing microRNAs can be persistently silenced in vivo through systemic delivery of anti-miRs, allowing for therapeutic modulation of disease mechanisms. Recent advances in understanding the mechanisms of cardiac injury and regeneration as well as strategies for promoting cardiac repair through modulation of intrinsic regenerative mechanisms will be discussed.
- © 2011 by American Heart Association, Inc.