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NIH Awards Three Grants for the Study of microRNAs in Cardiovascular Disease

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The National Institutes of Health this month set aside more than $750,000 to fund three grants focused on microRNAs and cardiovascular disease.

The grants are in addition to the nearly $2 million the agency put toward research into RNAi/miRNA delivery and RNA silencing in August (GSN 8/22/2013).

The first grant went to Beth Israel Deaconess Medical Center researcher Saumya Das to support his investigation into whether circulating miRNAs can be used to predict a patient's risk of experiencing adverse mechanical and electrical remodeling after a heart attack.

According to his grant's abstract, adverse remodeling following myocardial infarction is a major contributor to heart failure and sudden cardiac arrest, and biomarkers of these complications are "widely used" to stratify heart attack patients for additional medical intervention.

"However, current risk-stratification strategies lack adequate sensitivity and specificity," Das wrote in the abstract. "Thus, development of complementary biomarkers to predict adverse outcomes post-MI is needed for the appropriate and cost-effective applications of these advanced therapies."

A number of research groups have reported recently on the role of various miRNAs in heart remodeling, including a team from Harvard Medical School that linked miR-22 to cardiac hypertrophy and remodeling in response to stress. Also this year, a group of Italian researchers found that circulating levels of miR-33a can predict aortic valve replacement patients' risk of left ventricle hypertrophy.

With the NIH funding, Das and his colleagues aim to identify novel signatures of circulating miRNA that can determine susceptibility to arrhythmia and sudden cardiac arrest, as well as post-myocardial infarction heart failure.

They then plan to develop and test a digital PCR-based assay for the signatures in cohorts of patients with coronary artery disease and heart attacks.

The two-year grant began on Aug. 1 and is worth $500,000 in its first year.

The second grant was awarded to Emory University's Hanjoong Jo, who is studying the possible role of miRNAs on calcific aortic valve disease, or AV, a condition characterized by obstruction of outflow and aortic stenosis.

While originally believed to be a degenerative condition, AV is now known to be an "active inflammatory disease," according to Jo. The disease also occurs "preferentially" on the fibrosa side of aortic valve cusps, with the ventricularis side remaining "relatively healthy."

It is unknown what role shear stress — the force of friction of a fluid — plays in the disease, but Jo and colleagues hypothesize that disturbed flow conditions are present on the fibrosa and affect miRNA expression leading to AV-related inflammation and calcification.

Previously, Jo's lab identified shear-responsive miRNAs in human aortic valvular endothelial cells, although the function of these small, non-coding RNAs is unclear, he wrote in his grant's abstract. More recently, the lab discovered "side-dependent miRNAs from freshly isolated endothelial- enriched RNA" in porcine aortic valves," he noted. "From this work, we have identified miR-199a-5p, miR-214, and miR-486-5p as the top three shear- and/or side-dependent miRNAs."

Suspecting that these and other miRNAs may be behind AV, Jo aims to determine the role of mechanosensitive miRNAs in aortic valve endothelium in vitro and in pig models.

Shear- and side-dependent expression of miR-199a-5p, 214, and 486-5p will be validated in cultured aortic valvular endothelial cells and freshly isolated, endothelial-enriched RNA obtained from human and porcine hearts using qPCR and in situ hybridization, according to the abstract.

The role of the miRNAs in shear-sensitive endothelial function — including inflammation, migration, apoptosis, proliferation, and the cell cycle — will then be studied using gain- and loss-of-function studies.

Ex vivo porcine aortic valves will be used to determine the role of mechanosensitive miRNAs in the aortic valve endothelium. The pig valves will also be exposed to laminar and oscillatory sheer stress to identify shear- and side-dependent miRNAs.

Lastly, levels of the miRNAs will be modulated using antagonists and miRNA precursors in order to examine their impact on aortic valve inflammation and calcification in vivo in mouse models.

The grant began on Aug. 12 and runs until the end of May 2018. It is worth $462,131 in its first year.

Prasanna Krishnamurthy of Northwestern University received the last grant, which will help finance his studies into the influence of miRNAs on endothelial progenitor cell, or EPC, function in myocardial ischemia.

According to his grant's abstract, there is growing evidence indicating that aspects of the ischemic environment such as inflammation and oxidative stress can negatively affect stem cell function.

Research from Krishnamurthy's lab indicates that prolonged inflammation impairs the tube formation ability of EPCs in vitro, and that inflammation triggers the upregulation of several miRNAs associated with cell survival and angiogenesis — particularly miR-377 — in these cells, he noted in the abstract. Additionally, myocardial infarction was found to increase miR-377 expression in the myocardium, circulating EPCs, and plasma.

In other preliminary studies, transfection of EPCs with miR-377 precursors blocked expression of the kinase STK35, and mimics of the miRNA lowered EPC migration and vascular tube formation. When STK35 was knocked down in EPCs, Krishnamurthy and his colleagues observed a reduction in HDAC5 phosphorylation and an increase in GATA2 acetylation, which was associated with reduced expression of cytokines and growth factors, and reduced migration and vascular tube formation, the abstract states.

Lastly, in a mouse model of myocardial infarction, intramyocardial transplantation of ex vivo EPCs transfected with miR377 antagonists decreased cardiomyocyte apoptosis and infarct size, and enhanced neovascularization and left ventricle function.

In light of these data, Krishnamurthy speculates that the intramyocardial transplantation of miR-377-inhibited EPCs augments the cells' function by stimulating STK35-dependent phosphorylation and nuclear export of HDAC5, leading to increased GATA2-mediated transcription of genes that promote neovascularization and cardiomyocyte viability — all of which results in efficient myocardial repair after injury.

With the NIH funding, he plans to elucidate the role of miR-377 in EPC biology and function in vitro, determine the molecular mechanisms by which the miRNA controls STK35-meidated EPC function, and identify a critical role, if any, for the miRNA in EPC-mediated myocardial repair in a mouse model of myocardial infarction.

His grant, which began on Aug. 1 and runs for five years, is worth $367,710 in its first year.

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