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DZHK Paper of the month - july 2018

Chrono-pharmacological Targeting of the CCL2-CCR2 Axis Ameliorates Atherosclerosis.

The internal clock regulates all vital functions in the body including body temperature, blood pressure, and the release of certain hormones. Besides such physiological circadian oscillations, also disease manifestations can accumulate at a certain time of the day. In the context of cardiovascular diseases, acute coronary events predominantly occur in the morning hours, i.e. between 7 and 11 am. Based on such epidemiologic finding, a team led by DZHK Professor Oliver Soehnlein studied how the arterial recruitment of leukocytes, a process critically determining atheroprogression, is controlled by the circadian clock. In a mouse model of atherosclerosis the researchers showed that the adhesion on and recruitment into the arterial wall shows striking circadian oscillations: in the morning hours 3 times as many myeloid cells were recruited as compared to the evening hours. This effect is controlled by the rhythmic release of CCL2 from myeloid cells, which is immobilized on endothelial cells and consequently triggers firm leukocyte arrest. Interestingly, the peak in microvascular myeloid cell recruitment was found to be 12-hours phase-shifted. This opened a therapeutic window of opportunity, permitting the timed delivery of a CCR2 antagonist to hinder arterial leukocyte adhesion with limited interference in the microvasculature. In this study this principle was successfully tested in a mouse model of atherosclerosis. This study was in part funded by a DZHK 'Säule B' grant (cooperation with DZHK Professor Tanja Zeller). This study also represents a continuation of earlier findings of the Soehnlein Team, where they have identified novel therapeutic means to counteract arterial myeloid cell recruitment (e.g. Alard et al., Sci Transl Med, 2015; Ortega-Gomez et al., Circulation, 2016).

undefinedCell Metabolism (2018)

DZHK authors: Winter, Silvestre-Roig, Ortega-Gomez, Schumski, Drechsler, Immler, Sperandio, Zeller, Weber, Viola, Soehnlein

DZHK Paper of the month - may 2018

H19 Induces Abdominal Aortic Aneurysm Development and Progression.

An international team of researchers, led by Lars Magedefessel from the DZHK partner site Munich, Experimental Vascular Medicine @ TUM, was able to show that lncRNA H19, from the novel class of long non-coding RNA molecules (>200 base pairs; lncRNA)) is an important regulator of vascular smooth muscle cell survival (VSMC) and hence inhibition decreases growth and progression of abdominal aortic aneurysm (AAA).
AAA is a dilation of the abdominal aorta eventually leading to rupture which can currently only be treated by surgical means such as endovascular aortic repair (EVAR) or open repair. No causal therapy preventing and no medical therapy abrogating AAA development is available. lncRNAs are thought to be of great therapeutic potential due to their superordinate and well conserved role in regulatory processes. VSMCs are a crucial cellular component in AAA pathogenesis and increased apoptosis has been shown at rupture sites. In their current study, the authors show that H19 is highly expressed in AAA in human and mice and in vivo silencing significantly limits aneurysm growth in two different murine models. In a dynamic cell culture experiment H19 inhibition significantly reduced VSMC apoptosis. Hypoxia inducible factor 1 (HIF1a) is known to be crucial in the hypoxic micromilieu of the aneurysmatic aortic wall and was identified as the main downstream effector of H19 affecting cell survival.
These findings have recently been published in Circulation and harbor future therapeutic potential by local endovascular RNA-therapy.

undefinedCirculation, 2018.

DZHK authors: Li, Busch, Hofmann, Ramanujam, Dueck, Engelhardt, Boon, Eckstein, Maegdefessel

MiR-378 Controls Cardiac Hypertrophy by Combined Repression of MAP Kinase Pathway Factors

Transfection of miR-378 inhibits phenylephrine (PE)-induced hypertrophy of primary cardiomyocytes.

(April 2013) MicroRNAs (miRs) are small, noncoding RNAs that posttranscriptionally regulate gene expression. Thus, miRs have been shown to regulate many processes in health and disease, including cardiovascular disease. Using a method to screen libraries of mulitple synthetic miRs for the induction of cardiomyocyte hypertrophy, a hallmark of the myocardial stress response, a research team led by Stefan Engelhardt at the Institute of Pharmacology at TUM hat found the first evidence for an antihypertrophic activity of miR-378 in the myocardium. Subsequent analyses carried out by Jaya Ganesan, a PhD student at the Institute of Pharmacology and Toxicology now showed that miR-378 represses prohypertrophic signaling at four levels within the mitogen-activated protein kinase signaling pathway. MiR-378 was found to be downregulated both in animal models of myocardial disease and in human failing myocardium. Compensation for miR-378 downregulation in a cardiac disease model using viral gene transfer in vivo protected the heart against hypertrophy and dysfunction. Together, these data indicate effective interference of miR-378 with a key prohypertrophic signaling pathway. Targeted delivery of miR-378 to the heart may prove to be an effective therapeutic strategy in myocardial disease. For further reading see undefinedCirculation, published online April 26th, 2013.