Circulation research最新文献

{"title":"EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake.","authors":"Daniela Pirri, Siyu Tian, Blanca Tardajos-Ayllon, Sophie E Irving, Francesco Donati, Scott P Allen, Tadanori Mammoto, Gemma Vilahur, Lida Kabir, Jane Bennett, Yasmin Rasool, Charis Pericleous, Guianfranco Mazzei, Liam McAllan, William R Scott, Thomas Koestler, Urs Zingg, Graeme M Birdsey, Clint L Miller, Torsten Schenkel, Emily V Chambers, Mark J Dunning, Jovana Serbanovic-Canic, Francesco Botrè, Akiko Mammoto, Suowen Xu, Elena Osto, Weiping Han, Maria Fragiadaki, Paul C Evans","doi":"10.1161/CIRCRESAHA.123.324054","DOIUrl":"10.1161/CIRCRESAHA.123.324054","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, but its involvement in atherosclerosis remains unexplored. This study investigates the potential interplay between EPAS1, obesity, and atherosclerosis.</p><p><strong>Methods: </strong>Responses to shear stress were analyzed using cultured porcine aortic EC exposed to flow in vitro coupled with metabolic and molecular analyses and by en face immunostaining of murine aortic EC exposed to disturbed flow in vivo. Obesity and dyslipidemia were induced in mice via exposure to a high-fat diet or through Leptin gene deletion. The role of <i>Epas1</i> in atherosclerosis was evaluated by inducible endothelial <i>Epas1</i> deletion, followed by hypercholesterolemia induction (adeno-associated virus-PCSK9 [proprotein convertase subtilisin/kexin type 9]; high-fat diet).</p><p><strong>Results: </strong>En face staining revealed EPAS1 enrichment at sites of disturbed blood flow that are prone to atherosclerosis initiation. Obese mice exhibited substantial reduction in endothelial EPAS1 expression. Sulforaphane, a compound with known atheroprotective effects, restored EPAS1 expression and concurrently reduced plasma triglyceride levels in obese mice. Consistently, triglyceride derivatives (free fatty acids) suppressed EPAS1 in cultured EC by upregulating the negative regulator PHD2. Clinical observations revealed that reduced serum EPAS1 correlated with increased endothelial PHD2 and PHD3 in obese individuals. Functionally, endothelial EPAS1 deletion increased lesion formation in hypercholesterolemic mice, indicating an atheroprotective function. Mechanistic insights revealed that EPAS1 protects arteries by maintaining endothelial proliferation by positively regulating the expression of the fatty acid-handling molecules CD36 (cluster of differentiation 36) and LIPG (endothelial type lipase G) to increase fatty acid beta-oxidation.</p><p><strong>Conclusions: </strong>Endothelial EPAS1 attenuates atherosclerosis at sites of disturbed flow by maintaining EC proliferation via fatty acid uptake and metabolism. This endothelial repair pathway is inhibited in obesity, suggesting a novel triglyceride-PHD2 modulation pathway suppressing EPAS1 expression. These findings have implications for therapeutic strategies addressing vascular dysfunction in obesity.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"822-837"},"PeriodicalIF":16.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132007","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":"Deconstructing Regenerative Medicine: From Mechanistic Studies of Cell Therapy to Novel Bioinspired RNA Drugs.","authors":"Eduardo Marbán","doi":"10.1161/circresaha.124.323058","DOIUrl":"https://doi.org/10.1161/circresaha.124.323058","url":null,"abstract":"All Food and Drug Administration-approved noncoding RNA (ncRNA) drugs (n≈20) target known disease-causing molecular pathways by mechanisms such as antisense. In a fortuitous evolution of work on regenerative medicine, my coworkers and I inverted the RNA drug discovery process: first we identified natural disease-modifying ncRNAs, then used them as templates for new synthetic RNA drugs. Mechanism was probed only after bioactivity had been demonstrated. The journey began with the development of cardiosphere-derived cells (CDCs) for cardiac regeneration. While testing CDCs in a first-in-human trial, we discovered they worked indirectly: ncRNAs within CDC-secreted extracellular vesicles mediate the therapeutic benefits. The vast majority of such ncRNAs are fragments of unknown function. We chose several abundant ncRNA species from CDC-secreted extracellular vesicles, synthesized and screened each of them in vitro and in vivo. Those with exceptional disease-modifying bioactivity inspired new chemical entities that conform to the structural conventions of the Food and Drug Administration-approved ncRNA armamentarium. This discovery arc-Cell-Derived RNA from Extracellular vesicles for bioinspired Drug develOpment, or CREDO-has yielded various promising lead compounds, each of which works via a unique, and often novel, mechanism. The process relies on emergent insights to shape therapeutic development. The initial focus of our inquiry-CDCs-are now themselves in phase 3 testing for Duchenne muscular dystrophy and its associated cardiomyopathy. But the intravenous delivery strategy and the repetitive dosing protocol for CDCs, which have proven key to clinical success, both arose from systematic mechanistic inquiry. Meanwhile, emergent insights have led to multiple cell-free therapeutic candidates: CDC-secreted extracellular vesicles are in preclinical development for ventricular arrhythmias, while the CREDO-conceived RNA drugs are in translation for diseases ranging from myocarditis to scleroderma.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"22 1","pages":"877-885"},"PeriodicalIF":20.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328765","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":"Metabolic and Shear Stress Regulate Endothelial Epas1 in Atherosclerosis.","authors":"Judith C Sluimer","doi":"10.1161/circresaha.124.325131","DOIUrl":"https://doi.org/10.1161/circresaha.124.325131","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"7 1","pages":"838-840"},"PeriodicalIF":20.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328764","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":"Non-Contractile Stem Cell-Cardiomyocytes Preserve Post-Infarction Heart Function.","authors":"Elaheh Karbassi,Dasom Yoo,Amy M Martinson,Xiulan Yang,Hans Reinecke,Michael Regnier,Charles E Murry","doi":"10.1161/circresaha.124.325133","DOIUrl":"https://doi.org/10.1161/circresaha.124.325133","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"5 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246860","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000692","DOIUrl":"https://doi.org/10.1161/RES.0000000000000692","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 7","pages":"706-707"},"PeriodicalIF":16.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281156","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":"Targeting Cyclophilin A in the Cardiac Microenvironment Preserves Heart Function and Structure in Failing Hearts.","authors":"Manuel Sigle, Anne-Katrin Rohlfing, Melanie Cruz Santos, Timo Kopp, Konstantin Krutzke, Vincent Gidlund, Ferdinand Kollotzek, Julia Marzi, Saskia von Ungern-Sternberg, Antti Poso, Mathias Heikenwälder, Katja Schenke-Layland, Peter Seizer, Julia Möllmann, Nikolaus Marx, Robert Feil, Susanne Feil, Robert Lukowski, Oliver Borst, Tilman E Schäffer, Karin Anne Lydia Müller, Meinrad P Gawaz, David Heinzmann","doi":"10.1161/CIRCRESAHA.124.324812","DOIUrl":"10.1161/CIRCRESAHA.124.324812","url":null,"abstract":"<p><strong>Background: </strong>Cardiac hypertrophy is characterized by remodeling of the myocardium, which involves alterations in the ECM (extracellular matrix) and cardiomyocyte structure. These alterations critically contribute to impaired contractility and relaxation, ultimately leading to heart failure. Emerging evidence implicates that extracellular signaling molecules are critically involved in the pathogenesis of cardiac hypertrophy and remodeling. The immunophilin CyPA (cyclophilin A) has been identified as a potential culprit. In this study, we aimed to unravel the interplay between eCyPA (extracellular CyPA) and myocardial dysfunction and evaluate the therapeutic potential of inhibiting its extracellular accumulation to improve heart function.</p><p><strong>Methods: </strong>Employing a multidisciplinary approach encompassing in silico, in vitro, in vivo, and ex vivo experiments we studied a mouse model of cardiac hypertrophy and human heart specimen to decipher the interaction of CyPA and the cardiac microenvironment in highly relevant pre-/clinical settings. Myocardial expression of CyPA (immunohistology) and the inflammatory transcriptome (NanoString) was analyzed in human cardiac tissue derived from patients with nonischemic, noninflammatory congestive heart failure (n=187). These analyses were paralleled by a mouse model of Ang (angiotensin) II-induced heart failure, which was assessed by functional (echocardiography), structural (immunohistology, atomic force microscopy), and biomolecular (Raman spectroscopy) analyses. The effect of inhibiting eCyPA in the cardiac microenvironment was evaluated using a newly developed neutralizing anti-eCyPA monoclonal antibody.</p><p><strong>Results: </strong>We observed a significant accumulation of eCyPA in both human and murine-failing hearts. Importantly, higher eCyPA expression was associated with poor clinical outcomes in patients (<i>P</i>=0.043) and contractile dysfunction in mice (Pearson correlation coefficient, -0.73). Further, myocardial expression of eCyPA was critically associated with an increase in myocardial hypertrophy, inflammation, fibrosis, stiffness, and cardiac dysfunction in vivo. Antibody-based inhibition of eCyPA prevented (Ang II)-induced myocardial remodeling and dysfunction in mice.</p><p><strong>Conclusions: </strong>Our study provides strong evidence of the pathogenic role of eCyPA in remodeling, myocardial stiffening, and dysfunction in heart failure. The findings suggest that antibody-based inhibition of eCyPA may offer a novel therapeutic strategy for nonischemic heart failure. Further research is needed to evaluate the translational potential of these interventions in human patients with cardiac hypertrophy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"758-773"},"PeriodicalIF":16.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975201","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":"Microparticle Mediated Delivery of Apelin Improves Heart Function in Post Myocardial Infarction Mice.","authors":"Ling Tang, Huiliang Qiu, Bing Xu, Yajuan Su, Verah Nyarige, Pengsheng Li, Houjia Chen, Brady Killham, Jun Liao, Henderson Adam, Aaron Yang, Alexander Yu, Michelle Jang, Michael Rubart, Jingwei Xie, Wuqiang Zhu","doi":"10.1161/CIRCRESAHA.124.324608","DOIUrl":"10.1161/CIRCRESAHA.124.324608","url":null,"abstract":"<p><strong>Background: </strong>Apelin is an endogenous prepropeptide that regulates cardiac homeostasis and various physiological processes. Intravenous injection has been shown to improve cardiac contractility in patients with heart failure. However, its short half-life prevents studying its impact on left ventricular remodeling in the long term. Here, we aim to study whether microparticle-mediated slow release of apelin improves heart function and left ventricular remodeling in mice with myocardial infarction (MI).</p><p><strong>Methods: </strong>A cardiac patch was fabricated by embedding apelin-containing microparticles in a fibrin gel scaffold. MI was induced via permanent ligation of the left anterior descending coronary artery in adult C57BL/6J mice followed by epicardial patch placement immediately after (acute MI) or 28 days (chronic MI) post-MI. Four groups were included in this study, namely sham, MI, MI plus empty microparticle-embedded patch treatment, and MI plus apelin-containing microparticle-embedded patch treatment. Cardiac function was assessed by transthoracic echocardiography. Cardiomyocyte morphology, apoptosis, and cardiac fibrosis were evaluated by histology. Cardioprotective pathways were determined by RNA sequencing, quantitative polymerase chain reaction, and Western blot.</p><p><strong>Results: </strong>The level of endogenous apelin was largely reduced in the first 7 days after MI induction and it was normalized by day 28. Apelin-13 encapsulated in poly(lactic-co-glycolic acid) microparticles displayed a sustained release pattern for up to 28 days. Treatment with apelin-containing microparticle-embedded patch inhibited cardiac hypertrophy and reduced scar size in both acute and chronic MI models, which is associated with improved cardiac function. Data from cellular and molecular analyses showed that apelin inhibits the activation and proliferation of cardiac fibroblasts by preventing transforming growth factor-β-mediated activation of Smad2/3 (supporessor of mothers against decapentaplegic 2/3) and downstream profibrotic gene expression.</p><p><strong>Conclusions: </strong>Poly(lactic-co-glycolic acid) microparticles prolonged the apelin release time in the mouse hearts. Epicardial delivery of the apelin-containing microparticle-embedded patch protects mice from both acute and chronic MI-induced cardiac dysfunction, inhibits cardiac fibrosis, and improves left ventricular remodeling.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"777-798"},"PeriodicalIF":16.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981845","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":"Oxysterol Sensing Through GPR183 Triggers Endothelial Senescence in Hypertension.","authors":"Qingqing Chu, Yujia Li, Jichao Wu, Yanjiao Gao, Xiangyun Guo, Jing Li, Hang Lv, Min Liu, Wei Tang, Peng Zhan, Tao Zhang, Huili Hu, Hong Liu, Jinpeng Sun, Xiaojie Wang, Fan Yi","doi":"10.1161/CIRCRESAHA.124.324722","DOIUrl":"10.1161/CIRCRESAHA.124.324722","url":null,"abstract":"<p><strong>Background: </strong>Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown.</p><p><strong>Methods: </strong>Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study.</p><p><strong>Results: </strong>Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period circadian regulator 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP (cyclic adenosine monophosphate)/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice.</p><p><strong>Conclusions: </strong>This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"708-721"},"PeriodicalIF":16.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035419","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":"Restoring Atrial T-Tubules Augments Systolic Ca Upon Recovery From Heart Failure.","authors":"Jessica L Caldwell, Jessica D Clarke, Charlotte E R Smith, Christian Pinali, Callum J Quinn, Charles M Pearman, Aiste Adomaviciene, Emma J Radcliffe, Amy Watkins, Margaux A Horn, Elizabeth F Bode, George W P Madders, Mark Eisner, David A Eisner, Andrew W Trafford, Katharine M Dibb","doi":"10.1161/CIRCRESAHA.124.324601","DOIUrl":"10.1161/CIRCRESAHA.124.324601","url":null,"abstract":"<p><strong>Background: </strong>Transverse (t)-tubules drive the rapid and synchronous Ca²⁺ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca²⁺ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca²⁺.</p><p><strong>Methods: </strong>HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patch clamp, Ca²⁺, and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure.</p><p><strong>Results: </strong>Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca²⁺ release in the cell interior. Systolic Ca²⁺, <i>I</i>_Ca-L, sarcoplasmic reticulum Ca²⁺ content, and sarcoendoplasmic reticulum Ca²⁺ ATPase function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca²⁺ transient, the rate of Ca²⁺ removal, and the peak L-type Ca²⁺ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria.</p><p><strong>Conclusions: </strong>We show that recovery from HF restores atrial t-tubules, and this promotes recovery of <i>I</i>_Ca-L, sarcoplasmic reticulum Ca²⁺ content, and systolic Ca²⁺. We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"739-754"},"PeriodicalIF":16.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975200","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":"Targeting the I_Ks Channel PKA Phosphorylation Axis to Restore Its Function in High-Risk LQT1 Variants.","authors":"Ling Zhong, Zhenzhen Yan, Dexiang Jiang, Kuo-Chan Weng, Yue Ouyang, Hangyu Zhang, Xiaoqing Lin, Chenxin Xiao, Huaiyu Yang, Jing Yao, Xinjiang Kang, Changhe Wang, Chen Huang, Bing Shen, Sookja Kim Chung, Zhi-Hong Jiang, Wandi Zhu, Erwin Neher, Jonathan R Silva, Panpan Hou","doi":"10.1161/CIRCRESAHA.124.325009","DOIUrl":"10.1161/CIRCRESAHA.124.325009","url":null,"abstract":"<p><strong>Background: </strong>The KCNQ1+KCNE1 (I_Ks) potassium channel plays a crucial role in cardiac adaptation to stress, in which β-adrenergic stimulation phosphorylates the I_Ks channel through the cyclic adenosine monophosphate (cAMP)/PKA (protein kinase A) pathway. Phosphorylation increases the channel current and accelerates repolarization to adapt to an increased heart rate. Variants in KCNQ1 can cause long-QT syndrome type 1 (LQT1), and those with defective cAMP effects predispose patients to the highest risk of cardiac arrest and sudden death. However, the molecular connection between I_Ks channel phosphorylation and channel function, as well as why high-risk LQT1 mutations lose cAMP sensitivity, remain unclear.</p><p><strong>Methods: </strong>Regular patch clamp and voltage clamp fluorometry techniques were utilized to record pore opening and voltage sensor movement of wild-type and mutant KCNQ1/I_Ks channels. The clinical phenotypic penetrance of each LQT1 mutation was analyzed as a metric for assessing their clinical risk. The patient-specific-induced pluripotent stem-cell model was used to test mechanistic findings in physiological conditions.</p><p><strong>Results: </strong>By systematically elucidating mechanisms of a series of LQT1 variants that lack cAMP sensitivity, we identified molecular determinants of I_Ks channel regulation by phosphorylation. These key residues are distributed across the N-terminus of KCNQ1 extending to the central pore region of I_Ks. We refer to this pattern as the I_Ks channel PKA phosphorylation axis. Next, by examining LQT1 variants from clinical databases containing 10 579 LQT1 carriers, we found that the distribution of the most high-penetrance LQT1 variants extends across the I_Ks channel PKA phosphorylation axis, demonstrating its clinical relevance. Furthermore, we found that a small molecule, ML277, which binds at the center of the phosphorylation axis, rescues the defective cAMP effects of multiple high-risk LQT1 variants. This finding was then tested in high-risk patient-specific induced pluripotent stem cell-derived cardiomyocytes, where ML277 remarkably alleviates the beating abnormalities.</p><p><strong>Conclusions: </strong>Our findings not only elucidate the molecular mechanism of PKA-dependent I_Ks channel phosphorylation but also provide an effective antiarrhythmic strategy for patients with high-risk LQT1 variants.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"722-738"},"PeriodicalIF":16.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008352","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}