Heart disease and its manifestations, including coronary artery disease, myocardial infarction, congestive heart failure and cardiac hypertrophy, clearly presents a major health risk in the United States today. The cost to diagnose, treat and support patients suffering from these diseases is well into the billions of dollars. A particularly severe manifestation of heart disease is myocardial infarction. Myocardial infarction (MI), more commonly known as a heart attack, is a medical condition that occurs when the blood supply to a part of the heart is interrupted, most commonly due to rupture of a vulnerable plaque. The resulting ischemia or oxygen shortage causes damage and potential death of heart tissue. It is leading cause of death for both men and women throughout the world. In the United States alone, coronary heart disease is responsible for 1 in 5 deaths, and some 7,200,000 men and 6,000,000 women are living with some form of coronary heart disease. Of these, 1,200,000 people suffer a new or recurrent coronary attack every year, and about 40% of them die as a result of the attack. This means that roughly every 65 seconds, an American dies of a coronary event.
If impaired blood flow to the heart lasts long enough, it triggers an ischemic cascade, where the heart cells die from necrosis and a collagen scar forms in their place. Recent studies indicate that cell death from apoptosis also plays a role in the process of tissue damage subsequent to myocardial infarction. As a result, the patient's heart will be permanently damaged. This scar tissue also puts the patient at risk for potentially life threatening arrhythmias, and may result in the formation of a ventricular aneurysm that can rupture with catastrophic consequences. Injured heart tissue conducts electrical impulses more slowly than normal heart tissue. The difference in conduction velocity between injured and uninjured tissue can trigger re-entry or a feedback loop that is believed to be the cause of many lethal arrhythmias. Cardiac output and blood pressure may fall to dangerous levels, which can lead to further coronary ischemia and extension of the infarct.
In addition to the direct effects on the infarcted tissue, adjacent tissues in the borderzone around the infarct undergo a pathologic remodeling triggered by altered gene regulation. This remodeling results in further myocyte loss, hyperplasia and the further deposition of collagen in this region. Secondarily to the infarct, the remote myocardium responds to the infarct by cardiomyocyte hypertrophy and the onset of interstitial fibrosis. Thus, while the damage to the infarcted tissue maybe largely irreparable by the time an MI is diagnosed and addressed clinically, the further changes due to post-MI remodeling present a more likely point of therapeutic intervention. At present, however, there are no known treatments to address this aspect of heart disease.
Changes in gene expression and signaling pathways associated with post-MI remodeling have been intensively studied, with the goal of identifying therapeutic targets that might allow restoration of function to the injured heart. Recently, key roles of microRNAs in cardiac hypertrophy and heart failure have been described, pointing to a new mode of regulation of cardiac disease. MicroRNAs (miRNAs) are small, non-protein coding RNAs of about 18 to about 25 nucleotides in length that are derived from individual miRNA genes, from introns of protein coding genes, or from poly-cistronic transcripts that often encode multiple, closely related miRNAs. See review by Carrington et al. (Science, Vol. 301(5631):336-338, 2003). MiRNAs act as repressors of target mRNAs by promoting their degradation, when their sequences are perfectly complementary, or by inhibiting translation, when their sequences contain mismatches.
MiRNAs are transcribed by RNA polymerase II (pol II) or RNA polymerase III (pol III; see Qi et al. (2006) Cellular & Molecular Immunology, Vol. 3:411-419) and arise from initial transcripts, termed primary miRNA transcripts (pri-miRNAs), that are generally several thousand bases long. Pri-miRNAs are processed in the nucleus by the RNase Drosha into about 70- to about 100-nucleotide hairpin-shaped precursors (pre-miRNAs). Following transport to the cytoplasm, the hairpin pre-miRNA is further processed by Dicer to produce a double-stranded miRNA. The mature miRNA strand is then incorporated into the RNA-induced silencing complex (RISC), where it associates with its target mRNAs by base-pair complementarity. In the relatively rare cases in which a miRNA base pairs perfectly with an mRNA target, it promotes mRNA degradation. More commonly, miRNAs form imperfect heteroduplexes with target mRNAs, affecting either mRNA stability or inhibiting mRNA translation.
Based on a hand full of genetic studies in mice and humans, it is becoming increasingly clear that miRNAs are indeed actively involved in cardiac remodeling, growth, conductance, and contractility (reviewed in van Rooij and Olson (2007) Journal of Clinical Investigation, Vol. 117(9):2369-2376). Identification and characterization of miRNAs involved in cardiovascular disease is important for the development of novel therapeutic approaches for the treatment of cardiovascular disease diseases, such as myocardial infarction and heart failure.