Researchers prevent heart failure in mice
The hearts of the mice that possess more of the microRNAs 212 and 132 (on the right) are distinctly larger than the hearts of the normal mice (on the left). © Kamal Chowdhury / Max Planck Institute for Biophysical Chemistry

(Medical Xpress)—Cardiac stress, for example a heart attack or high blood pressure, frequently leads to pathological heart growth and subsequently to heart failure. Two tiny RNA molecules play a key role in this detrimental development in mice, as researchers at the Hannover Medical School and the Göttingen Max Planck Institute for Biophysical Chemistry have now discovered. When they inhibited one of those two specific molecules, they were able to protect the rodent against pathological heart growth and failure. With these findings, the scientists hope to be able to develop therapeutic approaches that can protect humans against heart failure.


Respiratory distress, fatigue, and attenuated performance are symptoms that can accompany heart failure. Germany-wide approximately 1.8 million people suffer from this disease. A reason for this can be an enlarged heart, a so-called . It may develop when the heart is subjected to permanent stress, for example, due to persistent or a valvular heart defect. In order to boost the pumping performance, the enlarge – a condition that frequently results in heart failure if not treated.

Two small RNA molecules tip the balance

A research team at the Göttingen Max Planck Institute for and the Hannover Medical School discovered that two small play a key role in the growth of heart muscle cells: the microRNAs miR-212 and miR-132. The scientists had observed that these microRNAs are more prevalent in the of mice suffering from cardiac hypertrophy. To determine the role that the two microRNAs play, the scientists bred genetically modified mice that had an abnormally large number of these molecules in their heart muscle cells. “These rodents developed cardiac hypertrophy and lived for only three to six months, whereas their healthy conspecifics had a normal healthy life-span of several years,” explained Dr. Kamal Chowdhury, researcher in the Department of Molecular Cell Biology at the Institute for Biophysical Chemistry. “For comparison, we also selectively switched off these microRNAs in other mice. These animals had a slightly smaller heart than their healthy conspecifics, but did not differ from them in behavior or life-span,” continued the biologist. The crucial point is when the scientists subjected the hearts of these mice to stress by narrowing the aorta, the mice did not develop cardiac hypertrophy – in contrast to normal mice.

A microRNA inhibitor protects mice against hypertrophy

The scientists were also able to protect normal mice against the disease. When they gave them a substance that selectively inhibits microRNA-132, no pathological cardiac growth occurred – even when the hearts of these mice were subjected to stress. “Thus, for the first time ever, we have found a molecular approach for treating pathological cardiac growth and heart failure in mice,” said the cardiologist Professor Dr. Dr. Thomas Thum, MD, Director of the Institute for Molecular and Translational Therapy Strategies (IMTTS) at the Hannover Medical School. With these findings, the researchers hope that they will be able to develop therapeutic approaches that can also protect humans against . “Such microRNA inhibitors, alone or in combination with conventional treatments, could represent a promising new therapeutic approach,” said Thum.

“In mice with an overdosage of the two microRNAs in their heart muscle cells, the cellular ‘recycling program’ is curbed,” explained Dr. Ahmet Ucar, who together with Shashi K. Gupta was responsible for the experiments. In this recycling process, the cell breaks down components that are damaged or no longer required and reuses their constituents – a vital process that, for example, ensures the organism’s survival under stress conditions.

In mice without the microRNAs -212 and 132, this recycling program is more active than in their normal conspecifics. Conceivably, the reduced cellular recycling could be a cause of the observed cardiac hypertrophy.

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More information: Ahmet Ucar, Shashi K. Gupta, Jan Fiedler, Erdem Erikci, Michal Kardasinski, Sandor Batkai, Seema Dangwal, Regalla Kumarswamy, Claudia Bang, Angelika Holzmann, Janet Remke, Massimiliano Caprio, Claudia Jentzsch, Stefan Engelhardt, Sabine Geisendorf, Carolina Glas, Thomas G. Hofmann, Michelle Nessling, Karsten Richter, Mario Schiffer, Lucie Carrier, L. Christian Napp, Johann Bauersachs, Kamal Chowdhury, Thomas Thum: The miRNA-212/132 family regulates both cardiac hypertrophy and autophagy. Nature Communications, 25. September 2012, doi: 10.1038/ncomms2090

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MiR-212 is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. Several targets for miR-132 have been described, including mediators of neurological development, synaptic transmission, inflammation and angiogenesis.

microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus

Newborn neurons in the dentate gyrus of the adult hippocampus rely upon cAMP response element binding protein (CREB) signaling for their differentiation into mature granule cells and their integration into the dentate network.

Among its many targets, the transcription factor CREB activates expression of a gene locus that produces two microRNAs, miR-132 and miR-212. In cultured cortical and hippocampal neurons, miR-132 functions downstream from CREB to mediate activity-dependent dendritic growth and spine formation in response to a variety of signaling pathways.

To investigate whether miR-132 and/or miR-212 contribute to the maturation of dendrites in newborn neurons in the adult hippocampus, we inserted LoxP sites surrounding the miR-212/132 locus and specifically targeted its deletion by stereotactically injecting a retrovirus expressing Cre recombinase.

Deletion of the miR-212/132 locus caused a dramatic decrease in dendrite length, arborization, and spine density. The miR-212/132 locus may express up to four distinct microRNAs, miR-132 and -212 and their reverse strands miR-132* and -212*. Using ratiometric microRNA sensors, we determined that miR-132 is the predominantly active product in hippocampal neurons. We conclude that miR-132 is required for normal dendrite maturation in newborn neurons in the adult hippocampus and suggest that this microRNA also may participate in other examples of CREB-mediated signaling.

Fate and plasticity of renin precursors in development and disease

Renin-expressing cells appear early in the embryo and are distributed broadly throughout the body as organogenesis ensues. Their appearance in the metanephric kidney is a relatively late event in comparison with other organs such as the fetal adrenal gland.

The functions of renin cells in extra renal tissues remain to be investigated. In the kidney, they participate locally in the assembly and branching of the renal arterial tree and later in the endocrine control of blood pressure and fluid-electrolyte homeostasis.

Interestingly, this endocrine function is accomplished by the remarkable plasticity of renin cell descendants along the kidney arterioles and glomeruli which are capable of reacquiring the renin phenotype in response to physiological demands, increasing circulating renin and maintaining homeostasis.

Given that renin cells are sensors of the status of the extracellular fluid and perfusion pressure, several signaling mechanisms (β-adrenergic receptors, Notch pathway, gap junctions and the renal baroreceptor) must be coordinated to ensure the maintenance of renin phenotype–and ultimately the availability of renin–during basal conditions and in response to homeostatic threats.

Notably, key transcriptional (Creb/CBP/p300, RBP-J) and posttranscriptional (miR-330, miR125b-5p) effectors of those signaling pathways are prominent in the regulation of renin cell identity. The next challenge, it seems, would be to understand how those factors coordinate their efforts to control the endocrine and contractile phenotypes of the myoepithelioid granulated renin-expressing cell.