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HomeCirculation ResearchVol. 132, No. 7In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Originally published30 Mar 2023https://doi.org/10.1161/RES.0000000000000608Circulation Research. 2023;132:791is related toDiscovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell PhenotypeDestabilization of Atherosclerotic Plaque by Bilirubin DeficiencyIntegrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte HypertrophyDiscovery of Trans-Acting Long Non-Coding RNAs that Regulate Smooth Muscle Cell Phenotype (p 795)Download figureDownload PowerPointShi et al identify long non-coding RNAs that regulate a phenotype switch in smooth muscle cells.Vascular smooth muscle cells (VSMCs) are a major contributing cell type in the progression of coronary artery disease (CAD) and become pathological by transitioning into a highly proliferative and migratory state. In searching for factors that regulate this transition—which could thus reveal ways to stop it—Shi and colleagues focused on the potential role of long non-coding RNAs (lncRNAs), many of which are regulatory in nature. Human coronary artery SMCs (HCASMCs) were subjected to various CAD stimuli and the expression changes of lncRNAs were analyzed. From the many differentially expressed lncRNAs, the team focused on two—ZIPPOR and TNS1-AS2, which were down- and up-regulated respectively relative to unstimulated cells. Interestingly, functional analysis of these two revealed that, despite being differently affected by CAD stimuli, repression of either led to similar effects in HCASMCs—increased migration and proliferation and increased expression of ZEB2, a master regulator of SMC phenotype transition. Both ZIPPOR and TNS1-AS2 were also found to interact directly with the ZEB2 protein to suppress its expression.While it is not known if these lncRNAs influence CAD progression, their suppression of SMC transition suggests such investigations are warranted.Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency (p 812)Download figureDownload PowerPointLow bilirubin aggravates atherosclerosis in mice, report Chen et al.Bilirubin is a yellowish pigment formed during the breakdown of red blood cells and is ordinarily processed by the liver and excreted. Liver dysfunction can cause a severe build-up of bilirubin resulting in jaundice, but a more modest elevation is associated with lower levels of cardiovascular disease (CVD). Indeed, people with higher levels of the pigment have a lower incidence of CVD, while coronary artery disease patients with especially low levels of bilirubin have less stable plaques and worse outcomes. To investigate how bilirubin might protect against CVD, Chen and colleagues engineered atherosclerosis-prone mice to produce less of the pigment, and compared them with control mice whose bilirubin levels were normal. A lack of bilirubin worsened atherosclerosis in multiple ways. For example, the test animals had increased levels of blood lipids, increased systemic inflammation and oxidative stress, evidence of endothelial dysfunction, and increased plaque instability. While the latter appeared to result from infiltration of inflammatory cells and increased expression of the pro-inflammatory enzyme, MPO, the molecular details behind bilirubin’s other effects are yet to be determined. Nonetheless, the findings lead the way for further research into whether modifying levels of bilirubin might help lower CVD risk.Integrated Proteomics Unveils Regulation of Cardiac Myocyte Hypertrophic Growth by a Nuclear cAMP Nanodomain Under the Control of PDE3A2 (p 828)Download figureDownload PowerPointA PDE3A2-controlled cAMP nanodomain regulates cardiomyocyte hypertrophy, say Subramaniam et al.Within cardiomyocytes, cAMP conveys beta-adrenergic receptor (βAR) signals to boost the strength and frequency of the heart’s contractions. But cAMP has other jobs within cells and its interactions with specific factors at specific subcellular nanodomains are thought to regulate task execution. One such factor is the enzyme PDE, which degrades cAMP. There are many different isoforms of PDE and they are thought to occupy and specify different nanodomains. Subramaniam and colleagues investigated the proteins associating with individual PDE isoforms when cardiomyocytes were stimulated with isoproterenol—a βAR agonist—and in this way discovered that βAR-activated PDE3A2 nanodomains associate with the transcription regulators SMAD4 and HDAC1, are located in the nucleus, and normally repress the expression of genes involved in hypertrophy. Sure enough, inhibition of PDE3 enabled cAMP-induced activation of hypertrophy genes and resulted in cardiomyocyte growth. PDE3 inhibitors are inotropic drugs that provide short term benefits to heart failure patients, but can worsen the condition if used long term. The finding that PDE3 inhibition led to cAMP-induced hypertrophy may thus partly explain the detrimental effects of such drugs on the heart, say the authors. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesDiscovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell PhenotypeHuitong Shi, et al. Circulation Research. 2023;132:795-811Destabilization of Atherosclerotic Plaque by Bilirubin DeficiencyWeiyu Chen, et al. Circulation Research. 2023;132:812-827Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte HypertrophyGunasekaran Subramaniam, et al. Circulation Research. 2023;132:828-848 March 31, 2023Vol 132, Issue 7 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000608PMID: 36996178 Originally publishedMarch 30, 2023 PDF download Advertisement