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HomeCirculation ResearchVol. 132, No. 4In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Originally published16 Feb 2023https://doi.org/10.1161/RES.0000000000000595Circulation Research. 2023;132:397is related toADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic AneurysmCirculating Extracellular Vesicle-Propagated microRNA Signature as a Vascular Calcification Factor in Chronic Kidney DiseaseCNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2CNP Promotes Anti-Arrhythmic Effects via Phosphodiesterase 2 (p 400)Download figureDownload PowerPointCachorro et al suggest new targets for treating arrhythmia in heart failure.If a person survives a myocardial infarction they remain at risk of eventual death from heart failure, with arrhythmia and sudden cardiac death being major causes. β-blockers are often used to mitigate arrhythmia in heart failure but have side effects such as hypotension, dizziness and brachycardia due to the heart’s reduced contractile force. In the search for novel targets and treatments, it was discovered that overexpression of the enzyme phosphodiesterase 2 (PDE2), involved in cardiomyocyte contractility among other things, protected mice from arrhythmia and death after infarction. Furthermore, in rats with acute myocardial ischemia, treatment with the vasoactive molecule c-type natriuretic protein (CNP) also reduced arrhythmia. Cachorro and colleagues now show that these two separate findings are in fact linked. Indeed, CNP treatment of mice induced PDE2 to reduce arrhythmia, they found. And, pharmaceutical or genetic inhibition of PDE2 activity, prevented CNP’s antiarrhythmic effects. Similar results were found in cultured cells, where CNP suppressed arrhythmogenic activity in mouse and human cardiomyocytes but not if PDE2 was inhibited. Together the results point to the CNP-PDE2 pathway as a possible target for new heart failure medications, say the team.ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm (p e78)Download figureDownload PowerPointMacrophage ADAR1 is a key driver of abdominal aortic aneurysm, report Cai et al.Abdominal aortic aneurysm (AAA) is a life-threatening chronic inflammatory disorder in which the wall of the vessel becomes progressively weakened leading to its localized bulging and potential rupture. It causes around 10,000 deaths annually in the US alone and with the exception of surgery there are no targeted treatments. An RNA processing protein called ADAR1, with RNA-editing and non-editing functions, has been linked to the disease, being found at raised levels in mouse and patient AAA lesions. Deletion of ADAR1 from smooth muscle cells (SMCs)—key cells of blood vessel walls—has also been shown to reduce AAA formation in mice. Now Cai and colleagues show that SMCs are not the only cells in which ADAR1 plays a role in AAA. Mice whose macrophages lacked ADAR1, were more resistant to AAA induction than were their wildtype counterparts. And the ADAR1-lacking macrophages were less inflammatory. Mechanistically, the team showed that ADAR1 normally enhances inflammation not by its RNA editing activity but by degrading another RNA protein called Drosha, which triggers a molecular cascade to inflammatory signaling. Finally, the team showed this ADAR1-Drosha interaction also exists in human AAA tissue, thus confirming the clinical relevance of their discoveries.Circulating Extracellular Vesicle-Propagated microRNA Signature a A Vascular Calcification Factor in Chronic Kidney Disease (p 415)Download figureDownload PowerPointExtracellular vesicles drive vascular calcification in chronic kidney disease, say Koide et al.Declining renal function in chronic kidney disease (CKD) is associated with the risk of cardiovascular issues such as vascular calcification. This link to calcification is partly due to the body’s altered handling of minerals. But, as Koide and colleagues show, extracellular vesicles (EVs), also play a role. EVs are membrane-bound packets released from cells that act as an inter-cellular and inter-organ communication system. Previously, the serum of CKD patients, but not healthy subjects, was shown to promote calcification of cultured vascular smooth muscle cells (VSMCs), but the agent responsible was unknown. Now the team show, serum from rats with CKD also promotes VSMC calcification, but not if EVs are depleted. Furthermore, injection of an EV inhibitor into CKD-model mice prevented vascular calcification. Analyses of EVs from CKD rodents revealed four microRNAs that were less abundant than in control EVs. And these miRNAs were found to target and suppress the pro-calcification activity of growth factor VEGFA. The same four miRNAs were reduced in human CKD patient EVs where levels of the RNAs correlated with kidney function. The authors thus conclude, these EV RNAs have the potential to be biomarkers of disease severity as well as targets for new therapies. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic AneurysmDunpeng Cai, et al. Circulation Research. 2023;132:e78-e93Circulating Extracellular Vesicle-Propagated microRNA Signature as a Vascular Calcification Factor in Chronic Kidney DiseaseTakaaki Koide, et al. Circulation Research. 2023;132:415-431CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2Eleder Cachorro, et al. Circulation Research. 2023;132:400-414 February 17, 2023Vol 132, Issue 4 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000595 Originally publishedFebruary 16, 2023 PDF download Advertisement