Heartwire-Medscape...
LA JOLLA, CA — A future generation of therapies for heart failure could depend on disruption of micro-RNA–mediated genetic machinery that affects cardiac myocyte structure and contractility. In a study primarily in mice but also in tissue from human failing hearts, injection of a tiny nucleotide that blocks a micro-RNA regulator of cellular calcium transport appeared to stem the progression of induced heart failure in the animal model[1].
The oligonucleotide was aimed at the micro-RNA miR-25, which was found to inhibit the sarcoplasmic-reticulum calcium-uptake gene SERCA2a. Reduced SERCA2a activity, which can lead to myocyte hypertrophy and poor cardiac contractility, is considered a mechanism of progressive symptomatic cardiomyopathy. Gene therapy of heart failure by intracoronary delivery of SERCA2a was explored in the CUPID trial, with promising preliminary results, as covered by heartwire .
As miR-25 was upregulated in mice with heart failure and in myocardium from failing human hearts and its blockade reversed HF progression in their experimental model, "inhibition of miR-25 may be a novel therapeutic strategy for the treatment of heart failure," conclude the authors, led by Christine Wahlquist (University of California San Diego [UCSD] and Sanford-Burnham Medical Research Institute, North Torrey Pines, CA), in their report published March 12, 2014 in Nature.
The group tested 875 micro-RNAs using a technique called high-throughput functional screening, for an ability to suppress SERCA2a. They identified several, which they then compared with a list of micro-RNAs already known to be upregulated in HF, co–senior author Dr Mark Mercola (UCSD and Sanford-Burnham Medical Research Institute) told heartwire .
"That's how we came upon miR-25, because it was the most potent micro-RNA that could suppress SERCA2a and was also upregulated in human heart failure," he said.
And indeed, it was upregulated in the mice with induced heart failure, where it delayed SERCA2a-mediated myocyte calcium uptake, and also in the tissue from human hearts explanted due to advanced heart failure.
Then the group injected the mice with an antisense oligonucleotide antagonist of miR-25 "and showed that it is able to not only inhibit miR-25, but that as a consequence it upregulates SERCA2a," Mercola said.
Left ventricular function and other hemodynamic markers in the mice had improved significantly within five months of the anti-miR-25 injections, compared with control mice. "It didn't just halt it, it actually reversed the effect. That was really encouraging."
There are potential advantages to targeting miR-25—a step upstream in the biochemical pathwayto SERCA2—rather than targeting SERCA2a itself, according to Mercola. Because the physiological effects of suppressing the micro-RNA are more pronounced than those of SERCA2a inhibition, miR-25 is likely to affect other targets, he speculated.
"So I think by targeting the micro-RNA to SERCA2, you're basically broadcasting the effects on other proteins involved in regulating contractility of the heart."