Abstract
We have reported that mast cell chymase, an angiotensin II-generating enzyme, is important in cardiovascular tissues. Recently, we developed a new chymase-specific inhibitory RNA aptamer, HA28, and we evaluated the effects of HA28 on cardiac function and the mortality rate after myocardial infarction. Echocardiographic parameters, such as the left ventricular ejection fraction, fractional shortening, and the ratio of early to late ventricular filling velocities, were significantly improved by treatment with HA28 after myocardial infarction. The mortality rate was significantly reduced in the HA28-treated group. Cardiac chymase activity and chymase gene expression were significantly higher in the vehicle-treated myocardial infarction group, and these were markedly suppressed in the HA28-treated myocardial infarction group. The present study provides the first evidence that a single-stranded RNA aptamer that is a chymase-specific inhibitor is very effective in the treatment of acute heart failure caused by myocardial infarction. Chymase may be a new therapeutic target in post-myocardial infarction pathophysiology.
Highlights
Myocardial infarction (MI) is caused by sudden occlusion of the coronary arteries, and the mortality rate following MI is rather high
Chymase can enzymatically cleave pro-matrix metalloproteinase (MMP)[9] and To determine the inhibitory efficacy of HA28 on chymase activity, hamlatent transforming growth factor (TGF)-b1 to their active ster chymase was purified from their cheek pouches, and the 50% inhibforms.[13,14,15]
The concept of using single-stranded nucleic acids as affinity molecules for protein or compound binding was initially described in 1990.16,17 The concept is based on the ability of short oligonucleotides to fold, in the presence of a target, into unique threedimensional (3D) structures that bind the target with high affinity and specificity.[18]
Summary
Myocardial infarction (MI) is caused by sudden occlusion of the coronary arteries, and the mortality rate following MI is rather high. After MI, patients may survive but most will develop heart failure (HF).[1] The poor prognosis after MI may be due to the following reasons. Acute occlusion of large coronary arteries damages the heart muscle, and it elicits a significant decrease in cardiac output (CO) and an increase in the occurrence of lethal arrhythmias resulting from an imbalance in cardiac electrical conduction. Ventricular fibrillation is the most important cause of sudden death following MI.[2,3] Second, human adult cardiomyocytes, which are in an advanced stage of terminal differentiation, can no longer proliferate, and, these cells cannot regenerate once they are lost in the heart after MI
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