Heart Disease: Heart Pump Function

One important hallmark of pathological cardiac hypertrophy and heart failure is the re-activation of a set of fetal cardiac genes, including those encoding atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and fetal isoforms of contractile proteins, such as skeletal -actin and
-myosin heavy chain (MHC). These genes are typically repressed post-natally and replaced by the expression of a set of adult cardiac genes. The consequences of fetal gene expression on cardiac function and remodeling, such as fibrosis, are not completely understood, but the up-regulation of -MHC, a slow ATPase, and down-regulation of -MHC, a fast contracting ATPase, in response to stress has been implicated in the diminution of cardiac function. Down-regulation of  and up-regulation of -MHC is a common response to cardiac injury irrespective of the species. Moreover, changes in the proportion of MHC isoforms correlate with the level of mechanical performance and efficiency of the heart. Relatively minor changes in the ratio of - to -MHC have been shown to have profound effects on cardiac contractility in humans and rodents and thus, much attention has focused on understanding the mechanisms that regulate - and -MHC switching and on potential approaches for therapeutically manipulating these mechanisms. Our 2007 publication in Science (van Rooij at al. Science 2007) showed that the -MHC gene encodes an intronic miR, miR-208, that is cardiac specific and dedicated to the cardiac stress response but not to normal cardiac development. These characteristics make miR-208 (and its down-stream effectors) an attractive therapeutic target for manipulating -MHC levels and cardiac remodeling during heart disease.

Heart Disease: Cell survival

Adult cardiomyocytes are terminally differentiated cells, and myocyte death is a common cause of many forms of cardiovascular disease. During cardiac ischemia and myocardial infarction, the increase in myocyte death in combination with an insufficient capacity of the heart to regenerate causes a decrease in cardiac function due to loss of viable tissue. In an effort to reduce infarct size in response to myocardial infarction, miRagen is exploring several miRNAs involved in regulating cell proliferation and cell viability.(van Rooij et al. Proc. Natl. Acad. Sci., 2008.)

Heart Disease: Fibrosis

Cardiac myocytes are normally surrounded by a fine network of collagen fibers. In response to pathological stress, cardiac fibroblasts and extracellular matrix proteins accumulate disproportionately and excessively. Cardiac fibrosis, which results in stiffening of the ventricular walls, diminished contractility and abnormalities in cardiac conductance, is a common consequence of numerous forms of heart disease, including pathological hypertrophy, volume overload and myocardial infarction. Phenotypically transformed fibroblast-like cells, termed myofibroblasts, are primarily responsible for fibrous tissue formation at the site of infarction. Thus, reversal of this process represents an important therapeutic target in post-MI management and heart failure. Fibrosis is also commonly associated with numerous other tissue disorders, such as liver, kidney and lung disease. One of miRagen’s lead miRNAs, miR-29, has been shown to regulate multiple components of the fibrotic response.(van Rooij et al. Proc. Natl. Acad. Sci., 2008.)

Reference: van Rooij E and Olson EN. JCI, 2007