HomeCirculation ResearchVol. 132, No. 1In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published5 Jan 2023https://doi.org/10.1161/RES.0000000000000587Circulation Research. 2023;132:2Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes (p e1)Download figureDownload PowerPointProbiotic delivery of ACE2 improves gut integrity and retinopathy in diabetic mice, show Prasad et al.Type 1 diabetes has a complex etiology and pathology that are not entirely understood. In addition to the destruction of insulin-producing cells, a recently discovered feature of the disease (in both model rodents and humans) is that levels of angiotensin-converting enzyme 2 (ACE2)—a component of the renin-angiotensin system controlling hemodynamics—can be unusually low in certain tissues. Moreover, genetic deficiency of ACE2 in rodents, exacerbates aspects of diabetes such as gut permeability, systemic inflammation and diabetic retinopathy, while boosting ACE2 levels has been shown to ameliorate diabetic retinopathy in mice. Prasad and colleagues now show that ACE2 treatment also improves gut integrity and systemic inflammation as well as retinopathy, and that certain improvements can even be seen once diabetes has long been established. Six months after the onset of diabetes in model mice, oral doses of Lactobacillus paracasei engineered to express humanized ACE2 led to a reversal of the animal’s gut barrier dysfunction and retinopathy, the team showed. Humans with diabetic retinopathy also displayed evidence of increased gut permeability and low ACE2 levels, suggesting they may benefit from a similar probiotic treatment developed for clinical use.Epsin Nanotherapy Regulates Cholesterol Transport to Fortify Atheroma Regression (p e22)Download figureDownload PowerPointSuppressing epsin activity could be a new way to treat atherosclerosis, suggest Cui et al.Epsins are a family of plasma membrane proteins that drive endocytosis. They are expressed at varying levels throughout the tissues of the body, and recent research shows they are unusually abundant on macrophages within atherosclerotic lesions. Furthermore, in mice, macrophage-specific epsin loss results in a reduction in foam cell formation and plaque development. Cui and colleagues now show this effect on foam cells is because epsins normally promote the internalization of lipids into macrophages through their endocytic activity. But that’s not all. The proteins also impede cholesterol efflux from macrophages further exacerbating lipid retention, the team found. It turns out, epsins drive the endocytosis and degradation of a cholesterol efflux factor called ABCG1. Importantly, these proatherogenic activities of epsins could be stopped. Using macrophage-targeting nanoparticles carrying epsin-specific silencing RNAs, the team could suppress production of the protein in cultured macrophages, and could reduce the size and number of plaques in atherosclerosis-prone mice (via injection of the nanoparticles). Together the results suggest blocking epsins, via nanotherapy or other means, could be a therapeutic approach to stopping or slowing atherosclerosis progression.Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart (p 10)Download figureDownload PowerPointBlocking 15-PGDH quells fibroblast activation to prevent cardiac fibrosis in mice, report Rubino et al.After a myocardial infarction, the initial scar that forms is essential for protecting the muscle from further damage and rupture. But, if the fibrosis is extensive or prolonged, it can limit muscle function and ultimately lead to heart failure and death. Finding treatments that prevent or reverse fibrosis is thus a desirable clinical goal. To identify inhibitors of profibrotic activity, Rubino and colleagues screened a library of 546 known non-toxic compounds for their ability to block growth factor-induced activation of rat fibroblast cells. Of the nine compounds with such activity, the team focused on one—SW033291—that had previously been shown to prevent lung fibrosis in mice. This compound inhibits the enzyme 15-PGDH, which degrades signaling molecules known as eicosanoids, which are involved in, among other things, tissue repair. Further experiments showed the compound could also switch off the activation state of human cardiac fibroblasts isolated from failing hearts. The team went on to show that infusing SW033291 into mice could ameliorate experimentally induced cardiac fibrosis and diastolic dysfunction. The findings thus identify 15-PDGH as a profibrotic factor that could serve as a therapeutic target for mitigating heart fibrosis and failure. Previous Back to top Next FiguresReferencesRelatedDetails January 6, 2023Vol 132, Issue 1 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000587 Originally publishedJanuary 5, 2023 PDF download Advertisement
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Oct 27, 2023
Wei Zhang + 6
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