Circ Res Research Articles

Abstract P354: Endothelial Sirt3 deficiency and SOD2 acetylation voids female protection from hypertension

The prevalence of hypertension in early adulthood among women is 3-times lower than in men; but with aging hypertension rate increases in women much steeper, and hypertensive vascular and kidney damage is significantly higher in women. Gender-specific aspects of hypertension are poorly understood and clinical studies did not show protection by estrogen hormone therapy. We found that human hypertension is linked to hyperacetylation of critical antioxidant and metabolic mitochondrial enzymes superoxide dismutase (SOD2) and long-chain acyl dehydrogenase (LCAD) due to vascular deficiency of mitochondrial deacetylase Sirt3. We hypothesized that endothelial Sirt3 depletion leads to the loss of female protective cardiovascular phenotype and exacerbates hypertension in female compared with male mice due to hyperacetylation of mitochondrial proteins. Indeed, infusion of angiotensin II in wild-type female mice showed protection of vascular metabolism, endothelial nitric oxide and lower blood pressure compared with male littermates which was coupled with reduced acetylation of mitochondrial LCAD and SOD2 in female mice. Endothelial specific Sirt3 knockout female mice showed increased mitochondrial acetylation, exacerbated angiotensin II-induced hypertension and higher blood pressure compared with male mice which models human hypertension. Hypertension is linked to SOD2 acetylation (Circ Res. 2020;126(4):439-452) which leads to SOD2 inactivation and vascular oxidative stress. We found that endothelial specific acetylation mimetic SOD2-K68Q knock-in female mice lost antihypertensive phenotype and had higher blood pressure compared with angiotensin II-infused male mice. These studies demonstrate critical role of mitochondrial acetylation in endothelial dysfunction and hypertension suggesting that female antihypertensive phenotype can be associated with reduced mitochondrial acetylation protecting mitochondrial and endothelial functions. It is conceivable that pharmacological targeting of mitochondrial metabolism and acetylation can rescue female cardiovascular protection and improve treatment of endothelial dysfunction and hypertension.

Abstract 31: Deacetylation Mimetic Mutation of Mitochondrial Superoxide Dismutase Attenuates Angiotensin II-Induced Hypertension by Protecting Against Oxidative Stress

Almost one-half of adults have hypertension, and blood pressure is poorly controlled in a third of patients despite the use of multiple drugs, likely due to mechanisms that are not affected by current treatments. Hypertension is linked to oxidative stress; however, common antioxidants are ineffective. Hypertension is associated with inactivation of key intrinsic mitochondrial antioxidant, superoxide dismutase 2 (SOD2), due to hyperacetylation but the role of specific SOD2 lysine residues has not been defined. Hypertension is associated with SOD2 acetylation at Lysine 68 (Circ Res. 2020;126(4):439-452) and we suggested that deacetylation mimetic mutation of K68 to Arginine in SOD2 inhibits vascular oxidative stress and attenuates hypertension. To test this hypothesis, we have developed a new deacetylation mimic SOD2-K68R mice. We performed in vivo studies in SOD2-K68R mice using angiotensin II (AngII) model of vascular dysfunction and hypertension. AngII infusion in wild-type mice induced vascular inflammation and oxidative stress, and increased blood pressure to 160 mm Hg. SOD2-K68R mutation completely prevented increase in mitochondrial superoxide, abrogated vascular oxidative stress, preserved endothelial nitric oxide production, protected vasorelaxation, and attenuated AngII-induced hypertension. AngII and cytokines contribute to vascular oxidative stress and hypertension. Treatment of wild-type aortas with AngII and cytokines in organoid culture increased mitochondrial superoxide by 2-fold which was completely prevented in aortas isolated from SOD2-K68R mice. Interestingly, ex vivo treatment of aortas isolated from hypertensive mice with Sirtuin activator resveratrol reduces SOD2 acetylation, inhibits mitochondrial superoxide, and rescues endothelial nitric oxide. These data support the important role of SOD2-K68 acetylation in vascular oxidative stress and pathogenesis of hypertension. We conclude that strategies to reduce SOD2 acetylation may have therapeutic potential in the treatment of vascular dysfunction and hypertension.

Correction to: Cell-Specific Mechanisms in the Heart of COVID-19 Patients.

HomeCirculation ResearchVol. 133, No. 1Correction to: Cell-Specific Mechanisms in the Heart of COVID-19 Patients Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: Cell-Specific Mechanisms in the Heart of COVID-19 Patients Originally published22 Jun 2023https://doi.org/10.1161/RES.0000000000000615Circulation Research. 2023;133:e18This article corrects the followingCell-Specific Mechanisms in the Heart of COVID-19 PatientsIn the article by Tsai et al, “Cell-Specific Mechanisms in the Heart of COVID-19 Patients,” which published in the May 12, 2023 issue of the journal (Circ Res. 2023;132:1290–1301. doi: 10.1161/CIRCRESAHA.123.321876), a correction was needed.The second author’s name was formatted incorrectly in the table of contents as Daniela Čiháková and should be written as Daniela Čiháková.The journal apologizes for this error.The corrected version of the table of contents is available at https://www.ahajournals.org/toc/res/132/10 eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesCell-Specific Mechanisms in the Heart of COVID-19 PatientsEmily J. Tsai, et al. Circulation Research. 2023;132:1290-1301 June 23, 2023Vol 133, Issue 1 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000615PMID: 37347837 Originally publishedJune 22, 2023 PDF download Advertisement

Correction to: LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin.

HomeCirculation ResearchAhead of PrintCorrection to: LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin Originally published23 May 2023https://doi.org/10.1161/RES.0000000000000612Circulation Research. 2023;0This article corrects the followingLncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein ArteridinIn the article by Yu et al. “LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin,” which published in the October 14, 2022 issue of the journal (Circ Res. 2022;131:768–787. doi: 10.1161/CIRCRESAHA.122.321080), corrections were needed.It was brought to our attention that in the published manuscript, the Figure 8H contains a representative western blot image for SM22 and α-SMA. Unfortunately, the SM22 image was inadvertently duplicated with data for α-SMA during the final figure preparation. We would like to state that the representative α-SMA image in the revised Figure 8H was not obtained from the same membrane as the Calponin, SM22, and GAPDH blots. Since the molecular weights of the target genes are quite near (α-SMA 42 kDa, Calponin 35 kDa, SM22 22 kDa, and GAPDH 37 kDa), all blots were performed on the same set of samples but on separate individual membranes from parallelly prepared protein gels, except that the signals for SM22 and GAPDH were obtained from the same membrane transferred from the same gel. Therefore, no proper loading control for the α-SMA and Calponin signals in Figure 8H. An identical protocol was performed to ensure equal loading across different blots, and all uncropped blots were uploaded as Supplemental Material.This correction does not change the outcomes or interpretation of the observations made in the published manuscript. Therefore, the original description and conclusion of the published manuscript remain unaffected.In addition, we would like to add funding information at the beginning of the Sources of Funding section, “This work was supported in part by the Program of Innovative Research Team by National Natural Science Foundation (81721001)”.The authors apologize for the error.The corrected version of this article is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCRESAHA.122.321080. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesLncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein ArteridinJunyi Yu, et al. Circulation Research. 2022;131:768-787 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000612PMID: 37218531 Originally publishedMay 23, 2023 PDF download Advertisement

Retraction of: Retraction of: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo.

HomeCirculation ResearchAhead of PrintRetraction of: Retraction of: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo Free AccessRetractionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessRetractionPDF/EPUBRetraction of: Retraction of: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo Originally published22 Mar 2023https://doi.org/10.1161/RES.0000000000000606Circulation Research. 2023;0This article is retracted byRetraction of: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In VivoThe following Retraction Notice of a Circulation Research article is being retracted:Retraction of: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo. Circ Res. 2022;131:e151. doi: 10.1161/RES.0000000000000578In October 2022, the following Circulation Research article was retracted based on a request by the University of Oklahoma Health Sciences Center due to data irregularities and image reuse in Figure 3:Cai Z, Ding Y, Zhang M, Lu Q, Wu S, Zhu H, Song P, Zou MH. Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo. Circ Res. 2016;119:422-33. doi: 10.1161/CIRCRESAHA.116.308301.Based on new information brought forward by Dr. Zhejun Cai, the University of Oklahoma Health Sciences Center revised its recommendation for the above article to correction instead of retraction.The editors are retracting this Retraction Notice in agreement with the University of Oklahoma. A separate Correction Notice has been published to update and correct Figure 3 in the original article. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesRetraction of: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In VivoCirculation Research. 2022;131:e151-e151 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000606PMID: 36946882 Originally publishedMarch 22, 2023 PDF download Advertisement

Correction to: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo.

HomeCirculation ResearchAhead of PrintCorrection to: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo Originally published22 Mar 2023https://doi.org/10.1161/RES.0000000000000607Circulation Research. 2023;0This article corrects the followingAblation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In VivoIn the article by Cai Z., et al, “Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo” which published in the July 22, 2016 issue of the journal (Circ Res. 2016;119:422-33. doi: 10.1161/CIRCRESAHA.116.308301), a correction is needed.Figure 3D, top left panel immunohistochemistry image labeled “ApoE-/-” with “Runx2” staining was mistakenly reused in Figure 4A, bottom left panel immunohistochemistry image labeled “ApoE-/-/AMPKα1f/f” with “Runx2” staining. This error does neither impact the main findings nor the main conclusion of this study.The correct version of Figure 3D has been updated with the corresponding original data.The authors apologize for the error. This correction has been made to the current online version of the article, which is available at https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.116.308301. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesAblation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In VivoZhejun Cai, et al. Circulation Research. 2016;119:422-433 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000607PMID: 36946881 Originally publishedMarch 22, 2023 PDF download Advertisement

Correction to: A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage.

HomeCirculation ResearchVol. 132, No. 5Correction to: A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage Originally published2 Mar 2023https://doi.org/10.1161/RES.0000000000000599Circulation Research. 2023;132:e95This article corrects the followingA Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal DamageIn the article by Alexander et al. “A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage,” which published in the October 14, 2022 issue of the journal (Circ Res. 2022;131:731–747. doi: 10.1161/CIRCRESAHA.121.320625), a correction was needed.During the editorial process, an error was introduced that change the abbreviation Trp to Trg in several places throughout the article. This has been corrected.The production team regrets these errors and state that this correction does not affect the original conclusions.The corrected version of this article is available at https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.121.320625. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesA Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal DamageMatthew R. Alexander, et al. Circulation Research. 2022;131:731-747 March 3, 2023Vol 132, Issue 5 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000599PMID: 36862815 Originally publishedMarch 2, 2023 PDF download Advertisement

Correction to: Downregulation of LAPTM4B Contributes to the Impairment of the Autophagic Flux via Unopposed Activation of mTORC1 Signaling During Myocardial Ischemia/Reperfusion Injury.

HomeCirculation ResearchVol. 132, No. 5Correction to: Downregulation of LAPTM4B Contributes to the Impairment of the Autophagic Flux via Unopposed Activation of mTORC1 Signaling During Myocardial Ischemia/Reperfusion Injury Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: Downregulation of LAPTM4B Contributes to the Impairment of the Autophagic Flux via Unopposed Activation of mTORC1 Signaling During Myocardial Ischemia/Reperfusion Injury Originally published2 Mar 2023https://doi.org/10.1161/RES.0000000000000597Circulation Research. 2023;132:e94This article corrects the followingDownregulation of LAPTM4B Contributes to the Impairment of the Autophagic Flux via Unopposed Activation of mTORC1 Signaling During Myocardial Ischemia/Reperfusion InjuryIn the article by Gu et al. entitled “Downregulation of LAPTM4B Contributes to the Impairment of the Autophagic Flux via Unopposed Activation of mTORC1 Signaling During Myocardial Ischemia/Reperfusion Injury,” which was published in the September 11, 2020 issue of the journal (Circ Res. 2020;127:e148–e165. doi: 10.1161/CIRCRESAHA.119.316388), corrections were needed.After concerns were raised in a PubPeer post about potential included duplicated images in image figures and blots, the authors thoroughly checked the data and provided an explanation. For Supplemental Figure IV-I, the WGA image in WT was accidentally presented as a ‘LAPTM4B-/-’ image during figure preparation. For Figure 4C, the representative blot image of GAPDH for Figure 7B was inadvertently duplicated to Figure 4C during figure processing. The authors identified a similar accidental mistake of P62 blot image in Figure 7B.The authors have provided original images and uncropped original gel scan to the journal for correction of these mistakes and updated the Figure 4C, Figure 7B and Supplemental Figure IV-I.The authors apologize for these errors and state that the corrections do not affect the original conclusions.The corrected version of this article is available at http://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.316388. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesDownregulation of LAPTM4B Contributes to the Impairment of the Autophagic Flux via Unopposed Activation of mTORC1 Signaling During Myocardial Ischemia/Reperfusion InjuryShanshan Gu, et al. Circulation Research. 2020;127:e148-e165 March 3, 2023Vol 132, Issue 5 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000597PMID: 36862816 Originally publishedMarch 2, 2023 PDF download Advertisement

Abstract 151: Genetic Factors And Outcomes After Stroke: A Preliminary Analysis Of The Strong Study

Introduction: Measures of genetic variation have provided insight into underlying biology and treatment approaches in a number of medical sciences. The STRONG (“The Stroke, sTress, RehabilitatiON, and Genetics Study”) Study evaluated genetic polymorphisms in relation to stroke recovery. Methods: The STRONG Study recruited patients with a new stroke from 28 U.S. stroke centers. Entry criteria included age ≥18 years and new ischemic stroke or intracerebral hemorrhage. Visit 1 was during acute admission; Visit 2, 90 days post-stroke; Visit 3, 6 mo post-stroke; and Visit 4, 12 mo post-stroke. Linear regression examined specific genotypes in relation to 2 primary outcomes (change in grip force from V1-V2 and global function (SIS-ADL) at V2) and 2 secondary outcomes (depression (PHQ-8) at V2 and cognitive function (t-MoCA) at V4). No correction for multiple comparisons is made below. Results: There were 763 patients enrolled from 2016-2020, with mean age 63.1±14.9 years, 41.1% female, median NIHSS score 4 [2-9]. Data were available in 510 patients at Visit 2 and 482 at Visit 4. The BDNF val66met polymorphism (rs6265) was related to poorer V4 MoCA score (p=0.01). Presence of ApoE4 was not related to any endpoint. For the dopamine polygene score, a relationship with lower score (reduced dopamine neurotransmission) and greater depression (higher V2 PHQ-8 score) was suggested (p=0.1). A polymorphism (rs1842681) associated with chronic mRS score in a prior GWAS study (Neurology. 2019;92:e1271) was related to STRONG Study d90 mRS score (p=0.05). Three polymorphisms (rs76221407, rs150862264, rs182008837) associated with 3-mo mRS score in a separate GWAS study (Circ Res. 2019;124:114) were not related to STRONG Study d90 mRS score (p=.71-.78). ConclusionS: The STRONG Study collected genotypes and detailed longitudinal behavioral data during the year following stroke. Data do not support several hypotheses. However, presence of the BDNF val66met polymorphism may be related to poorer cognitive outcome. Lower dopamine gene score showed a trend with greater depression, consistent with a prior publication. Current findings support a prior GWAS finding for chronic mRS score. Genetics studies provide insights into inter-subject differences in recovery after stroke.

Con: General Anesthesia Should No Longer Routinely Be Used for Transfemoral Transcatheter Aortic Valve Replacement

Transcatheter aortic valve replacement (TAVR) procedures were introduced in the early 2000s as an alternative to surgical aortic valve replacement (SAVR) in high-risk patients who were not surgical candidates. 1 Bourantas CV Serruys PW. Evolution of transcatheter aortic valve replacement. Circ Res. 2014; 114: 1037-1051 Crossref PubMed Scopus (54) Google Scholar The safety of the procedure improved over time as the procedure became more widespread and new deployment devices, valves, and percutaneous access were refined. 1 Bourantas CV Serruys PW. Evolution of transcatheter aortic valve replacement. Circ Res. 2014; 114: 1037-1051 Crossref PubMed Scopus (54) Google Scholar Encouraging outcomes, such as a decreased hospital length of stay and improved morbidity, have expanded access to TAVRs to populations deemed intermediate and low-risk for SAVR. 2 Carroll JD Mack MJ Vemulapalli S et al. STS-ACC TVT Registry of transcatheter aortic valve replacement. J Am Coll Cardiol. 2020; 76: 2492-2516 Crossref PubMed Scopus (294) Google Scholar According to the Society of Thoracic Surgery-American College of Cardiology Transcatheter Valve Therapy Registry, >70,000 TAVRs were performed in the United States in 2019, surpassing the number of SAVRs that year. 2 Carroll JD Mack MJ Vemulapalli S et al. STS-ACC TVT Registry of transcatheter aortic valve replacement. J Am Coll Cardiol. 2020; 76: 2492-2516 Crossref PubMed Scopus (294) Google Scholar The most common access site is increasingly transfemoral (95% in 2019), and the need for conversion to open cardiac surgery with the use of cardiopulmonary bypass has significantly decreased from 4% to 0.4% since the introduction of TAVRs. 2 Carroll JD Mack MJ Vemulapalli S et al. STS-ACC TVT Registry of transcatheter aortic valve replacement. J Am Coll Cardiol. 2020; 76: 2492-2516 Crossref PubMed Scopus (294) Google Scholar The focus of care surrounding TAVRs is now shifting to a minimally invasive approach with shorter procedure time, shorter hospital length of stay, and reduced costs. 3 Sawan MA Calhoun AE Grubb KJ et al. Update on minimalist TAVR care pathways: Approaches to care in 2022. Curr Cardiol Rep. 2022; 24: 1179-1187 Crossref PubMed Scopus (2) Google Scholar Although both conscious sedation and general anesthesia techniques can be used for TAVR procedures, the authors assert that conscious sedation is superior as it helps achieve these goals with potentially less risk.

SYK Kinase As a Master Regulator of Netosis

Background NETosis is a key neutrophil response to tissue damage and pathogens. It is a form of programmed cell death resulting in chromatin decondensation, histone citrullination and controlled extracellular release of chromosomal DNA. This DNA complexed to a variety of noxious proteins such as elastase, myeloperoxidase and citrullinated histones is called neutrophil extracellular traps (NETs). NETs are largely responsible for anti-viral and anti-microbial effects of neutrophils during infection. NETs can cause significant tissue damage in various pathological conditions such as severe infections (COVID-19 and others) and multiple autoimmune and autoinflammatory diseases characterized by hyperactivation of innate and adaptive immune systems. Together with concurrent platelet and coagulation cascade activation, NETs formation is known to drive coagulopathy and thrombosis often associated with sterile inflammation in autoimmune and autoinflammatory diseases and in severe COVID-19 (Y. Zhou et al.). Strong correlation between NETosis biomarkers and thrombosis has been established in patients with many thrombogenic diseases (Mołek et al.; Martos et al.). Inhibition of NETs using DNAse treatment, protein arginine deiminase 4 (PAD4) inhibitors, or PAD4 knockout results in decrease in thrombi formation in vitro and in vivo (Franck et al.; Martinod et al.; Yan et al.). NETs release induced by plasma from severe COVID-19 patients in normal human neutrophils can be blocked in the presence of the highly selective SYK inhibitor R406, an active metabolite of the immune thrombocytopenia drug fostamatinib (Strich et al.). The inhibitor is thought to block antibody- and viral particle-mediated neutrophil activation through FcgRIIA and C-type lectin receptors (CLRs) controlled by SYK. Methods/Results To further elucidate the role of SYK kinase in NETosis, we have analyzed healthy human neutrophil responses to various stimuli in the presence of multiple commercially available SYK inhibitors using the Incucyte Live-Cell Analysis System. As expected, R406 potently inhibited immune complex induced NETosis mediated by FcgRIIA. To our surprise, every SYK inhibitor we've tested selectively blocked seemingly unrelated LPS-mediated TLR4-dependent NETs release. The effect was clearly specific as SYK inhibition had no effect on SYK-independent LPS-induced cytokine secretion or on cell proliferation at concentrations far exceeding those fully blocking NETosis. In contrast to SYK inhibitors, neither a selective JAK inhibitor nor dexamethasone had a significant effect on NETs release under the same assay conditions. Moreover, R406 potently inhibited NETs production in response to hydrogen peroxide and monosodium urate (MSU) crystal treatment of healthy neutrophils. The mechanisms behind the ability of SYK inhibitors to block NETs formation in response to such a plethora of unrelated stimuli will be further discussed. Conclusions The ability of SYK inhibitors to block both NETosis and platelet activation (in case of platelets, via CLEC2 and GPVI - two receptors involved in thrombosis yet dispensable for hemostasis) is consistent with possibility that, in addition to anti-inflammatory properties, SYK inhibition has potential anti-thrombotic effects (Harbi et al.). Indeed, the latter might be behind the lower than expected rates of thrombotic events in ITP patients observed in clinical trials of fostamatinib (Cooper et al.). References Yilu Zhou et al. Front Cardiovasc Med. 2021 Dec 2;8:786387. Laura Martos et al. Int J Mol Sci. 2020 Aug 6;21(16):5651. Patrycja Mołek et al. Thromb Res. 2022 May;213:1-7. Grégory Franck et al. Circ Res. 2018 June 22;123(1): 33-42. Kimberly Martinod et al. Proc Natl Acad Sci U S A. 2013 May 21;110(21):8674-8679. Yanyan Yan et al. Aging (Albany NY). 2019 Sep 15;11(17):6951-6959. Jeffrey R Strich et al. J Infect Dis. 2021 Mar 15;223(6):981-984. Maan H. Harbi et al. Int J Mol Sci. 2022 Jul;23(13):6982. Nichola Cooper et al. Ther Adv Hematol. 2021 Apr 30;12:20406207211010875

Correction to: Gut dysbiosis promotes preeclampsia by regulating macrophages and trophoblasts.

HomeCirculation ResearchVol. 131, No. 11Correction to: Gut dysbiosis promotes preeclampsia by regulating macrophages and trophoblasts Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: Gut dysbiosis promotes preeclampsia by regulating macrophages and trophoblasts Originally published10 Nov 2022https://doi.org/10.1161/RES.0000000000000581Circulation Research. 2022;131:e169This article corrects the followingGut Dysbiosis Promotes Preeclampsia by Regulating Macrophages and TrophoblastsIn the article by Jin et al, “Gut dysbiosis promotes preeclampsia by regulating macrophages and trophoblasts,” which published in the September 2 issue of the journal (Circ Res. 2022;131:492–506. doi: https://doi.org/10.1161/CIRCRESAHA.122.320771), a correction was needed.The author affiliations are currently written as:Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences (J.J., Y.Z., Z.Z., Z.T., X.W., C.Z., Q.Z.). State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine (J.J., Y.Z., Z.Z., Z.T., X.W., C.Z., Q.Z.). Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China (J.J., Y.Z., Z.Z., Z.T., X.W., C.Z., Q.Z.).The affiliations should be corrected to:Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China (J.J., Y.Z., Z.Z., Z.T., X.W., C.Z., Q.Z.).The authors apologize for this error.The corrected version of this article is available at:https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.122.320771 Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesGut Dysbiosis Promotes Preeclampsia by Regulating Macrophages and TrophoblastsJiajia Jin, et al. Circulation Research. 2022;131:492-506 November 11, 2022Vol 131, Issue 11 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000581PMID: 36356116 Originally publishedNovember 10, 2022 PDF download Advertisement

Retraction of: Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo.

The following Circulation Research article is being retracted: Cai Z, Ding Y, Zhang M, Lu Q, Wu S, Zhu H, Song P, Zou MH. Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo . Circ Res. 2016;119:422–433. doi: 10.1161/CIRCRESAHA.116.308301. The editors received a request from the University of Oklahoma Health Sciences Center to retract the above referenced article due to data irregularities and image reuse in Figure 3 that affect the results and conclusions reported in the manuscript. Specifically, the following irregularities were found: In Figure 3D, the top left panel immunohistochemistry image labeled “ApoE – / – with “Runx2” staining was reused in Figure 4A, bottom left panel immunohistochemistry image labeled “ApoE – / – /AMPKα1 f/f ” with “Runx2” staining. The editors are retracting this article in agreement with the University of Oklahoma. The authors do not agree to the retraction.

OCCULT NONCOMPACTION CARDIOMYOPATHY LEADING TO CARDIOGENIC SHOCK: AN INFREQUENT YET DEADLY DIAGNOSIS

OCCULT NONCOMPACTION CARDIOMYOPATHY LEADING TO CARDIOGENIC SHOCK: AN INFREQUENT YET DEADLY DIAGNOSIS

Shear stress and intravascular pressure effects on vascular dynamics: two-phase blood flow in elastic microvessels accounting for the passive stresses.

We study the steady hemodynamics in physiological elastic microvessels proposing an advanced fluid-structure interaction model. The arteriolar tissue is modeled as a two-layer fiber-reinforced hyperelastic material representing its Media and Adventitia layers. The constitutive model employed (Holzapfel et al. in J Elast 61:1-48, 2000) is parametrized via available data on stress-strain experiments for arterioles. The model is completed by simulating the blood/plasma flow in the lumen, using the thixotropic elasto-viscoplastic model in its core, and the linear Phan-Thien and Tanner viscoelastic model in its annular part. The Cell-Free Layer (CFL) and the Fåhraeus and Fåhraeus-Lindqvist effects are considered via analytical expressions based on experimental data (Giannokostas et al. in Materials (Basel) 14:367, 2021b). The coupling between tissue deformation and blood flow is achieved through the experimentally verified pressure-shear hypothesis (Pries et al. Circ Res 77:1017-1023, 1995). Our calculations confirm that the increase in the reference inner radius produces larger expansion. Also, by increasing the intraluminal pressure, the thinning of the walls is more pronounced and it may reach 40% of the initial thickness. Comparing our predictions with those in rigid-wall microtubes, we conclude that apart from the vital importance of vasodilation, there is an up to 25% reduction in wall shear stress. The passive vasodilation contributes to the decrease in the tissue stress fields and affects the hemodynamic features such as the CFL thickness, reducing the plasma layer when blood flows in vessels with elastic walls, in quantitative agreement with previous experiments. Our calculations verify the correctness of the pressure-shear hypothesis but not that of the Laplace law.

Abstract P2012: GRK2-Induced Cardiomyocyte AdipoR1 Phosphorylation Blocks Adipocytes-Derived Exosomes Cardioprotection Against Ischemic Heart Failure

Background: Despite significant reduction in acute MI death, ischemic heart failure (IHF) and resultant death continually escalate with incompletely understood mechanism. We recently reported that adipocyte-derived exosomes (ADp-Exo) protect heart from acute MI/R injury. However, it remains unknown whether and how cardiomyocytes (CM) response to ADp-Exo is altered during the chronic phase of MI, negatively impacting IHF development. Methods and Results: Intramyocardial injection of ADp-Exo (isolated from epididymal fat pad) immediately after MI (90 min MI/4 weeks reperfusion) significantly attenuated post-MI remodeling. However, the protective effects were completely lost when ADp-Exo were administered 1 week after MI. To identify the molecular mechanisms responsible for ADp-Exo cardioprotection and its alteration during chronic MI, a series of in vitro experiments were performed. Adiponectin (APN), a potent cardioprotective adipokine, was detected on the surface of ADp-Exo (Exo-flow kit). Treatment of CM with ADp-Exo activated multiple cell salvage kinases (e.g., ACC, ERK and AMPK). These effects were lost in APN neutralization antibody pre-incubated ADp-Exo or ADp-Exo from APNKO mice, suggesting Exo surface APN may mediate ADp-Exo cardioprotection. Moreover, ADp-Exo cell salvage kinase activation effect was absent in CM from AdipoR1KO mice or GRK2 transfected CM, suggesting GRK2-induced AdipoR1 phosphorylation at Ser 205 (as we demonstrated in Circulation, 2015 and Circ Res, 2022) is likely responsible for incapability of ADp-Exo protection during post-MI remodeling. To obtain direct evidence supporting this novel hypothesis, AdipoR1 S205A or AdipoR1 S205E (pseudo-phosphorylation) mice were generated. ADp-Exo cardioprotection was restored in AdipoR1 S205A mice, even when they were administered 1 week after MI. In contrast, ADp-Exo cardioprotection was lost in AdipoR1 S205E mice, even when they were administered immediately after MI. Conclusions: We demonstrate for the first time that, APN located on the surface of ADp-Exo acts as the critical executor of ADp-CM communication, mediating ADp-Exo cardioprotection. GRK2-induced CM AdipoR1 phosphorylation blocks ADp-Exo protective action, contributing to IHF progression.

From the Literature

From the Literature

Correction to: De Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous Malformation.

HomeCirculation ResearchVol. 130, No. 1Correction to: De Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous Malformation Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: De Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous Malformation Originally published7 Jan 2022https://doi.org/10.1161/RES.0000000000000524Circulation Research. 2022;130:234This article corrects the followingDe Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous MalformationIn the article by Li et al, “De Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous Malformation,” which published in the October 15, 2021 issue of the journal (Circ Res. 2021;129:825–839. doi: 10.1161/CIRCRESAHA.121.319004), a correction was needed.There was an error in the Abstract and Introduction: The definition of AVM was incorrectly displayed as “arteriovenous-malformation-like” when it should have been “arteriovenous-malformation”.The journal apologizes for the error.The corrected version of this article is available at www.ahajournals.org/doi/10.1161/CIRCRESAHA.121.319004. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesDe Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous MalformationHao Li, et al. Circulation Research. 2021;129:825-839 January 7, 2022Vol 130, Issue 1 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000524PMID: 34995139 Originally publishedJanuary 7, 2022 PDF download Advertisement

Corticosteroid Receptors in Cardiac Health and Disease.

Nuclear receptors play a central role in both energy metabolism and cardiomyocyte death and survival in the heart. Recent evidence suggests they may also influence cardiomyocyte endowment. Although several members of the nuclear receptor family play key roles in heart maturation (including thyroid hormone receptors) and cardiac metabolism, here, the focus will be on the corticosteroid receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). The heart is an important target for the actions of corticosteroids, yet the homeostatic role of GR and MR in the healthy heart has been elusive. However, MR antagonists are important in the treatment of heart failure, a condition associated with mitochondrial dysfunction and energy failure in cardiomyocytes leading to mitochondria-initiated cardiomyocyte death (Ingwall and Weiss, Circ Res 95:135-145, 2014; Ingwall , Cardiovasc Res 81:412-419, 2009; Zhou and Tian , J Clin Invest 128:3716-3726, 2018). In contrast, animal studies suggest GR activation in cardiomyocytes has a cardioprotective role, including in heart failure.

DNMT3A and TET2 mutant Clonal Hematopoiesis May Drive a Proinflammatory State and Predict Enhanced Response to Immune Checkpoint Inhibitors

DNMT3A and TET2 mutant Clonal Hematopoiesis May Drive a Proinflammatory State and Predict Enhanced Response to Immune Checkpoint Inhibitors