Resolving a Catch-22 in Cardiac Gene Regulation

Abstract

You have a big heart.” These five words have almost as many implications. Being big hearted can describe a generous and giving nature. In a different context, Secretariat's heart was unusually large because he carried an X-linked gene1 conferring on him rare physiological attributes that in 1973 propelled him to thoroughbred horse racing's Triple Crown. When the same declaration occurs between cardiologist and patient, however, the connotation is overwhelmingly negative. Heart enlargement from cardiac hypertrophy or dilated cardiomyopathy is a powerful positive predictor of morbidity and mortality.2,3 Accordingly, efforts to more fully understand the molecular underpinnings of structural and functional cardiac remodeling have been a major focus of basic cardiovascular research since genetic reprogramming was first mechanistically linked to cardiac hypertrophy.4,5 Over the past 25 years major transcriptional controls for pathological cardiac gene expression have been defined and suggested novel genetic approaches to control or reverse hypertrophy.6 Article see p 2751 Our conceptual understanding of the relationship between cardiac gene expression and physiotype derives from the common view that transcriptional regulation of genes determines expression of messenger RNAs (mRNA) that encode myocardial proteins. Recent evidence for epigenetic regulation by microRNAs has revised this linear paradigm. MicroRNAs adjust transcript abundance by binding to complementary sequences of target mRNAs, inducing their destruction, or blocking their translation (reviewed in 7). Clinical and experimental evidence implicates microRNAs as an important component of genetic reprogramming in cardiac hypertrophy and heart failure. Ongoing efforts targeting microRNAs show potential therapeutic efficacy.8 Based primarily on large-scale microarray analyses, it is estimated that the heart expresses 300 to 400 microRNAs (of ≈1000 known) at meaningful levels. Of these, levels of >200 cardiac microRNAs are regulated in cardiac pressure overload, ischemia, or failure.9 The details of these regulatory events will …