HomeCirculation ResearchVol. 132, No. 6In 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 Mar 2023https://doi.org/10.1161/RES.0000000000000602Circulation Research. 2023;132:671sFlt1-Induced Preeclampsia Causes Persistent Post-partum Sensitivity to Hypertension Via Smooth Muscle Mineralocorticoid Receptor (p 674)Download figureDownload PowerPointThe mineralocorticoid receptor is central to post-preeclampsia hypertension, say Biwer et al.Preeclampsia (PE) is a serious, sometimes fatal, condition affecting around five percent of pregnancies and is characterized by high blood pressure and kidney dysfunction that starts after the twentieth gestational week. While delivery of the baby usually resolves PE, survivors have an increased risk of cardiovascular issues including increased sensitivity to hypertensive stimuli. Because the smooth muscle cell mineralocorticoid receptor (SMC-MR) is a key factor in the body’s response to these stimuli, Biwer and colleagues investigated its role in post-PE hypertension sensitivity. First, they created a mouse model of PE, wherein the growth factor receptor sFlt1 was overexpressed in late gestation. This factor is found at high levels in patients with PE and its overproduction in pregnant mice results in PE-like physiology. Compared with control animals, the PE mice had increased post-partum sensitivity to hypertensive stimuli (angiotensin II and salt) as well as aortic stiffness and vascular constriction. If the PE-model mice lacked SMC-MR, however, they were protected from these post-partum effects. Together with supporting cell culture experiments, these results highlight SMC-MR’s role in post-PE hypertension and suggest blocking the receptor may lower the risk.Hypoxia Sensing of β-Adrenergic Receptor Is Regulated by Endosomal PI3Kγ (p 690)Download figureDownload PowerPointSun et al unravel the molecular consequences of acute hypoxia in the heart.Reduced oxygen availability in the myocardium resulting from ischemic heart disease is known to impair functioning of the cardiomyocyte beta-adrenergic receptors (βARs)—critical controllers of the heart’s rhythm and output. A full understanding of this molecular pathology is lacking, however. Sun and colleagues now show that hypoxia-induced βAR dysfunction is mediated in large part by the membrane-associated lipid kinase PI3Kγ. After several hours of hypoxia exposure, βAR phosphorylation (a mark of dysfunction) was significantly increased in human and mouse cells, particularly within the endosomes (a site of βAR recycling). Endosomal activity of PI3Kγ was increased too, the team showed, and this resulted in the repression of endosomal PP2A—a protein phosphatase that normally dephosphorylates, and thus reactivates, βAR. Confirming the role of PI3Kγ, the team showed that mice lacking the kinase were protected from the heart damaging effects of acute hypoxia—including reduced ejection fraction and cardiac remodeling—that were seen in wild type animals. The authors thus conclude that preserving myocardial βAR function, via the inhibition of PI3Kγ, may be a therapeutic approach for safeguarding the heart in situations where the tissue is acutely starved of oxygen.Dectin-1 Acts as a Non-Classical Receptor of Ang II to Induce Cardiac Remodeling (p 707)Download figureDownload PowerPointDectin-1 binds angiotensin II and mediates heart failure pathology, say Ye et al.Angiotensin II (AngII) is a vasoconstricting hormone central to blood pressure regulation and which contributes to heart failure progression through its promotion of cardiomyocyte hypertrophy, arrythmia and fibrosis. The latter involves activation of inflammatory macrophages, but the precise molecular details of AngII’s effects on these cells is unknown. Ye and colleagues now show that the macrophage receptor Dectin-1, which normally functions as part of the innate immune response, mediates AngII’s inflammatory effects. Previous work had shown Dectin-1 is increased in the heart following ischemia-reperfusion injury, and the new work shows levels of the receptor are also elevated following chronic AngII infusion. Wild type mice receiving such an infusion developed signs of heart failure including reduced ejection fraction, enlarged left ventricle diameter, cardiac hypertrophy, inflammation and fibrosis, but these signs were notably reduced in animals genetically engineered to lack Dectin-1. The team went on to show AngII directly interacts with Dectin-1 and identified the particular residues involved. The importance of this AngII-Dectin-1 interaction in heart pathology, suggests that preventing it could potentially slow the progression to heart failure, say the team. Previous Back to top Next FiguresReferencesRelatedDetails March 17, 2023Vol 132, Issue 6 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000602 Originally publishedMarch 16, 2023 PDF download Advertisement
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