Cardiovascular Research最新文献

{"title":"Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation.","authors":"Srividya Velagapudi,Melroy X Miranda,Priyanka Adla,Simon Kraler,Shafeeq A Mohammed,Shekhar Baki,Jerome Robert,Lucia Rohrer,Hwan Lee,Hyun-Duk Jang,Slayman Obeid,Anne Tailleux,Bart Staels,Naresh Babu V Sepuri,Francesco Paneni,Ravi Kumar Gutti,Arnold von Eckardstein,Hyo-Soo Kim,Alexander Akhmedov,Giovanni G Camici,Thomas F Lüscher","doi":"10.1093/cvr/cvaf087","DOIUrl":"https://doi.org/10.1093/cvr/cvaf087","url":null,"abstract":"AIMSLow-density lipoprotein (LDL)-cholesterol is causally involved in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Pharmacological activation of the intracellular NAD + -dependent deacetylase Sirtuin-1 (SIRT1) reduces plasma LDL-cholesterol levels by increasing hepatic LDL-receptor (LDLR) expression, which intriguingly associates with atheroprotective effects. Recent studies have identified the presence of SIRT1 in plasma, however, its effects remain elusive. We found that plasma levels of SIRT1 to be decreased in atherosclerotic mice compared with wild-type controls and aimed to investigate the therapeutic potential of systemic SIRT1 restoration on lipid metabolism and plaque burden in atherosclerotic mice and dissect the underlying molecular mechanisms involved.METHODS AND RESULTSTwelve-week-old apolipoprotein E-deficient (ApoE-/-) mice fed a high-cholesterol diet (1.25% w/w) were randomized to receive recombinant murine SIRT1(rmSIRT1) (n = 6; 0.3 mg/kg BW i.p.) or vehicle (n = 6; PBS) every third day over 4 weeks. Boosting systemic SIRT1 levels increased hepatic LDLR protein expression, reduced plasma LDL-cholesterol levels and decreased plaque progression in ApoE-/- mice. Yet, rmSIRT1 treatment did not change hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) expression but notably increased its deacetylated levels. Mechanistically, rmSirt1 directly bound to hepatic PCSK9 thereby promoting PCSK9 deacetylation involving 3 sites, namely Lys243, Lys421, and Lys506, as shown by mass spectrometric analyses. In vitro mutagenesis to triple deacetylation mimetic (3KR) reduced SIRT1-induced PCSK9 activity, as evidenced by increased cellular binding and association of 125I-LDL to hepatic LDLR. Finally, plasma levels of SIRT1 and PCSK9 were assessed at baseline in patients with acute coronary syndromes. In these patients, plasma SIRT1 levels correlated inversely with PCSK9 with high SIRT1 levels conferring a reduced risk of major adverse cardiovascular events (MACE).CONCLUSIONSIRT1 directly binds hepatic PCSK9 and decreases its activity by deacetylation, thereby enhancing LDL-cholesterol clearance by hepatic LDLR upregulation. Boosting circulating SIRT1 exerts atheroprotective effects in mice, with high levels associating with improved prognosis in patients with established ASCVD.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"19 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Right stellate ganglion stimulation modulates arrhythmogenesis in acute left lateral ventricular ischemia","authors":"Joseph E Hadaya, Bastiaan J D Boukens, Michiel J Janse, Steven Cha, Al-Hassan Dajani, Ronald Challita, Ruben Coronel, Jeffrey L Ardell, Kalyanam Shivkumar, Veronique M F Meijborg","doi":"10.1093/cvr/cvaf121","DOIUrl":"https://doi.org/10.1093/cvr/cvaf121","url":null,"abstract":"Aim Acute myocardial ischemia causes fatal arrhythmias as result of a flow of ‘injury current’. Left stellate ganglion stimulation (LSGS) modulates the injury current and is arrhythmogenic during left anterior ventricular wall ischemia. The role of right stellate ganglion stimulation (RSGS) in arrhythmogenesis is unclear. We hypothesized, that RSGS is proarrhythmic during left lateral ventricular wall ischemia. Methods and results In 11 anesthetized female pigs, ventricular repolarization was measured in unipolar epicardial electrograms from the left lateral ventricular wall. Seven subsequent episodes of acute ischemia (5 minutes) were produced by occlusion of the circumflex coronary artery (CX), separated by 20 minutes of reperfusion. The second occlusion served as a control. After 3 minutes of ischemia during the third occlusion, LSGS was initiated for 30 seconds. In the 4th occlusion, RSGS was performed. After decentralization of both left and right stellate ganglia and vagal nerves, LSGS and RSGS were initiated (6th and 7th occlusion). RSGS during ischemia was more arrhythmogenic than LSGS or control with more spontaneous ventricular premature beats (3-5 minutes of ischemia) and 2 instances of ventricular fibrillation. The LSGS-induced effect on repolarization was absent in myocardium that had been ischemic for 3 minutes by CX occlusion. Conclusions LSGS-induced repolarization shortening is absent in ischemic myocardium. RSGS was more arrhythmogenic following CX-occlusion than LSGS or control. These data demonstrate that the arrhythmogenic influence of RSGS or LSGS is contingent on the location of ischemic zone supporting the clinical findings that bilateral sympathectomy is superior to left sympathectomy alone.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"15 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-C Motif chemokine receptor-2 blockade ameliorates pulmonary hypertension in rats and synergizes with a pulmonary vasodilator.","authors":"Naoki Tsuboya, Hirofumi Sawada, Yoshihide Mitani, Hironori Oshita, Kazunobu Ohya, Mami Takeoka, Jane Chanda Kabwe, Yoshiki Miyasaka, Hiromasa Ito, Noriko Yodoya, Hiroyuki Ohashi, Junko Maruyama, Ryuji Okamoto, Tomoji Mashimo, Kaoru Dohi, Yuhei Nishimura, Kazuo Maruyama, Masahiro Hirayama","doi":"10.1093/cvr/cvae244","DOIUrl":"10.1093/cvr/cvae244","url":null,"abstract":"<p><strong>Aims: </strong>We investigated whether the disruption of C-C motif chemokine receptor (CCR) 2 may attenuate the development of pulmonary arterial hypertension (PAH) in any rat models with the reversal of the associated pro-inflammatory state and vascular dysfunction, and synergize with a conventional pulmonary vasodilator.</p><p><strong>Methods and results: </strong>Using Ccr2(-/-) rats generated by CRISPR/Cas9, we investigated pulmonary hypertension (PH) in Ccr2(+/+) or Ccr2(-/-) rats treated with monocrotaline (MCT), SU5416/hypoxia (SuHx) and chronic hypoxia (CH). Ccr2(-/-) decreased the right ventricular systolic pressure, an index of right ventricular hypertrophy and mortality rate, and reversed increased expression of inflammatory cytokines/chemokines [interleukin-6, tumour necrosis factor-α, C-C motif chemokine receptor (CCL)-2, interleukin-1β, transforming growth factor-β] in rats 3weeks after MCT injection, but not in SuHx or CH models. Consistently, Ccr2(-/-) decreased indices of pulmonary vascular diseases (PVDs) and perivascular macrophage infiltration, as well as reversed impaired bone morphogenetic protein receptor type 2 signalling, increased endothelial apoptosis and impaired nitric oxide signalling and decreased phosphodiesterase-5 (PDE5) expression in lungs in MCT-treated rats. Gene expression of receptors for prostaglandin I2 and endothelin was not changed by Ccr2(-/-) in MCT-treated rats. In cultured pulmonary arterial smooth muscle cells (PASMCs), Ccr2(-/-) suppressed CCL2-induced hyperproliferation and dedifferentiation as well as reversed CCL2-induced decrease in PDE5 expression. The whole-genome RNA sequencing analysis identified differentially expressed genes in CCL2-stimulated Ccr2(-/-) PASMCs, which are related to the regulation of cellular differentiation and contraction. Based on studies in rats and cultured PASMCs, we investigated whether a PDE5 inhibitor, tadalafil, synergizes with Ccr2(-/-). Tadalafil administration ameliorated PH and PVDs in MCT-treated Ccr2(-/-) rats but not in Ccr2(+/+) rats. Tadalafil further improved survival in MCT-treated Ccr2(-/-) rats.</p><p><strong>Conclusion: </strong>The present findings demonstrated that CCR2 disruption ameliorated PAH in MCT-treated rats, which was associated with the reversal of dysregulated inflammatory pathways and vascular dysfunction and synergized with tadalafil. These findings suggest that CCR2 may be a therapeutic target in intractable PAH patients with a certain CCR2-related inflammatory phenotype and refractory to conventional pulmonary vasodilators.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1076-1090"},"PeriodicalIF":10.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial insulin-like growth factor-1 signalling regulates vascular barrier function and atherogenesis.","authors":"Michael Drozd, Alexander-Francisco Bruns, Nadira Y Yuldasheva, Azhar Maqbool, Hema Viswambharan, Anna Skromna, Natallia Makava, Chew W Cheng, Piruthivi Sukumar, Lauren Eades, Andrew M N Walker, Kathryn J Griffin, Stacey Galloway, Nicole T Watt, Natalie Haywood, Victoria Palin, Nele Warmke, Helen Imrie, Katherine Bridge, David J Beech, Stephen B Wheatcroft, Mark T Kearney, Richard M Cubbon","doi":"10.1093/cvr/cvaf055","DOIUrl":"10.1093/cvr/cvaf055","url":null,"abstract":"<p><strong>Aims: </strong>Progressive deposition of cholesterol in the arterial wall characterizes atherosclerosis, which underpins most cases of myocardial infarction and stroke. Insulin-like growth factor-1 (IGF-1) is a hormone that regulates systemic growth and metabolism and possesses anti-atherosclerotic properties. We asked whether endothelial-restricted augmentation of IGF-1 signalling is sufficient to suppress atherogenesis.</p><p><strong>Methods and results: </strong>We generated mice with endothelial-restricted over-expression of human wild-type (WT) IGF-1R (hIGFREO/ApoE-/-) or a signalling-defective K1003R mutant human IGF-1R (mIGFREO/ApoE-/-) and compared them with their respective ApoE-/- littermates. hIGFREO/ApoE-/- had less atherosclerosis, circulating leucocytes, arterial cholesterol uptake, and vascular leakage in multiple organs, whereas mIGFREO/ApoE-/- did not exhibit these phenomena. Over-expressing WT IGF-1R in human umbilical vein endothelial cells (HUVECs) altered the localization of tight junction proteins and reduced paracellular leakage across their monolayers, whilst over-expression of K1003R IGF-1R did not have these effects. Moreover, only over-expression of WT IGF-1R reduced HUVEC internalization of cholesterol-rich low-density lipoprotein particles and increased their association of these particles with clathrin, but not caveolin-1, implicating it in vesicular uptake of lipoproteins. Endothelial over-expression of WT vs. K1003R IGF-1R also reduced expression of YAP/TAZ target genes and nuclear localization of TAZ, which may be relevant to its impact on vascular barrier and atherogenesis.</p><p><strong>Conclusion: </strong>Endothelial IGF-1 signalling modulates both para- and transcellular vascular barrier function. Beyond reducing atherosclerosis, this could have relevance to many diseases associated with abnormal vascular permeability.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1108-1120"},"PeriodicalIF":10.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging role of Cellular communication network factor 2 as a guardian of smooth muscle cell phenotype and vascular integrity.","authors":"Jannik Hjortshøj Larsen, Lasse Bach Steffensen","doi":"10.1093/cvr/cvaf015","DOIUrl":"10.1093/cvr/cvaf015","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"985-987"},"PeriodicalIF":10.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-C motif chemokine receptor 2 and phosphodiesterase type 5 inhibition in immune subphenotypes: a step toward personalized treatment for pulmonary arterial hypertension?","authors":"Christian J Goossen, Patrick J Pagano","doi":"10.1093/cvr/cvaf081","DOIUrl":"10.1093/cvr/cvaf081","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"980-982"},"PeriodicalIF":10.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet derived RNAs: a new regulatory marker for vascular inflammation?","authors":"Shinya Goto,Masayuki Oki,Shinichi Goto","doi":"10.1093/cvr/cvaf124","DOIUrl":"https://doi.org/10.1093/cvr/cvaf124","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"21 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From lipids and inflammation to artificial intelligence-driven therapeutics: the 93rd European atherosclerosis society (EAS) congress 2025 in focus.","authors":"Danila Gurgone,Jeffrey Kroon,Charalambos Antoniades","doi":"10.1093/cvr/cvaf110","DOIUrl":"https://doi.org/10.1093/cvr/cvaf110","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"20 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of trimetazidine dihydrochloride therapy on myocardial external efficiency in preclinical individuals with a hypertrophic cardiomyopathy pathogenic variant: results of the ENERGY trial","authors":"Beau Olivier van Driel, Stephan A C Schoonvelde, Sonia Borodzicz-Jazdzyk, Roy Huurman, Julia Visch, Lourens Robbers, Hans Harms, Judith Verhagen, Alexa Vermeer, Joost van den Aardweg, Albert C van Rossum, Tjeerd Germans, Michelle Michels, Jolanda van der Velden","doi":"10.1093/cvr/cvaf120","DOIUrl":"https://doi.org/10.1093/cvr/cvaf120","url":null,"abstract":"Aims Previous studies have shown that individuals with a hypertrophic cardiomyopathy (HCM) pathogenic variant (PV) or likely pathogenic variant (LPV) without a HCM phenotype (PV/LPV carrier) have decreased myocardial external efficiency (MEE), which is thought to be a key pathomechanism in the onset and progression of HCM. Metabolic treatments improved exercise capacity in HCM patients, but evidence that such drugs correct reduced MEE is lacking. The ENERGY trial is a double-blind, placebo-controlled randomized clinical trial to define if the metabolic drug trimetazidine (TMZ) corrects reduced MEE in PV/LPV carriers for HCM. Methods and results 51 MYBPC3 or MYH7 PV/LPV carriers were screened after which 40 were included and randomized into a treatment group (n=20) or placebo group (n=20) stratified for sex. Participants were treated with TMZ 20mg or placebo three times daily during eight weeks. The main outcome of this study was MEE as measured by [11C]-acetate positron emission tomography/computed tomography (PET/CT) and cardiac magnetic resonance (CMR) scan. Secondary outcomes were exercise parameters as measured by cardio-pulmonary exercise testing (CPET). Drug safety was monitored by (serious) adverse event registration. Treatment groups were comparable in terms of age, sex, body mass index, P/LP gene variant, and echocardiographic parameters without significant differences. Baseline CMR parameters and MEE were not significantly different between treatment groups. Eight weeks of treatment with TMZ did not significantly alter MEE compared to placebo. The mean MEE changed from 30.3±3.8 to 29.8±4.3 percent in the placebo group and from 30.1±4 to 29.1±4 percent in the TMZ group. Compared to placebo, the TMZ group did not have a significantly different MEE (difference -0.44, 95% interaction CI, -2.863 to 1.986, P=0.68). The mean V’O2max as a percentage of predicted V’O2max (V’O2max %pred) changed from 108±17 to 111±19 (95% CI, -6 to 10, P=0.84) percent in the placebo group and from 105±17 to 113±14 (95% CI, 1 to 16, P=0.03) percent in the TMZ group. After adjustment for baseline, the TMZ group had a significantly increased V’O2max %pred (difference 6.37, 95% interaction CI, -3 to 16, P=0.04). Conclusion The ENERGY trial is the first proof-of-concept randomized controlled trial to test the hypothesis that TMZ improves MEE in MYBPC3 or MYH7 PV/LPV carriers. We conclude that metabolic therapy with TMZ may not correct the P/LP gene variant-related decrease in MEE. Trial registration Netherlands Trial Register NL7492 (URL https://onderzoekmetmensen.nl/nl/trial/25078)","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"71 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Women in cardiology: how to meet European Society of Cardiology gender policy.","authors":"Agnieszka Tycinska,Jaroslaw Drozdz,Anna Fijalowska,Renata Glowczynska,Agnieszka Gorgon-Komor,Marcin Kurzyna,Katarzyna Mizia-Stec,Agnieszka Pawlak,Janina Stepinska,Piotr Szymanski,Agnieszka Wolczenko,Robert Zymlinski","doi":"10.1093/cvr/cvaf107","DOIUrl":"https://doi.org/10.1093/cvr/cvaf107","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"19 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}