BACKGROUNDIn high shear rate blood flow, thrombosis often starts with platelet adhesion via the interaction between VWF (von Willebrand factor) and its platelet receptor, the GPIb-IX (glycoprotein Ib-IX) complex. GPIb-IX also induces intracellular signals, mediating VWF-induced platelet activation and enhancing thrombin- and collagen-induced platelet activation. GPIb-IX signaling requires SFK (Src family kinase) Lyn. However, it remains unclear how Lyn mediates GPIb-IX signaling, whether Lyn directly binds to GPIb-IX, and if it is possible to target this signaling node for developing novel antithrombotics.METHODS AND RESULTSLyn directly binds to GPIb (glycoprotein Ib) β subunit between amino acids 144 to 161 at the transmembrane/cytoplasmic domain interface, and this binding is critical for not only the extracellular GPIb-IX ligand-induced intracellular signaling but also transmits outbound signals enhancing VWF-GPIb-IX interaction. A small peptide, mPLβ, derived from the Lyn binding site in GPIbβ, inhibited VWF-induced or α-thrombin-induced GPIbβ-Lyn interaction, Lyn/SFK activation, stable platelet adhesion and aggregation, and, notably, reduced GPIb-mediated platelet adhesion to VWF even in the presence of integrin inhibitors. Biomembrane force probe study further shows that mPLβ reduces the VWF-A1 domain-GPIb adhesion frequency and inhibits force-induced A1-mediated intraplatelet calcium elevation. Importantly, mPLβ formulated as a high-loading peptide nanoparticle inhibited platelet adhesion/aggregation induced by collagen and in vivo arterial thrombosis with a mild effect in prolonging bleeding time.CONCLUSIONSDirect binding of Lyn to GPIbβ mediates 2-way GPIb-IX signaling to activate platelets and modulate VWF-GPIb interaction. Lyn-mediated GPIb-IX signaling is critical for platelet adhesion and aggregation induced by VWF and collagen and in arterial thrombosis. Targeting the Lyn-GPIbβ interaction, thus, has the potential for treating GPIb-IX-dependent thrombosis.
{"title":"Direct Binding of Lyn to GPIbβ Transmits Two-Way GPIb-IX Signaling to Stimulate Platelet Activation and VWF Binding.","authors":"Yaping Zhang,Ying Liang,Amir Hossein Kazemipour Ashkezari,Can Wang,Claire Chang,Yanyan Bai,Xin Huang,Andrew Mack,Haotian Yang,Peiwen Cong,Ni Cheng,Cheng Zhu,Xiaoping Du","doi":"10.1161/circresaha.124.325616","DOIUrl":"https://doi.org/10.1161/circresaha.124.325616","url":null,"abstract":"BACKGROUNDIn high shear rate blood flow, thrombosis often starts with platelet adhesion via the interaction between VWF (von Willebrand factor) and its platelet receptor, the GPIb-IX (glycoprotein Ib-IX) complex. GPIb-IX also induces intracellular signals, mediating VWF-induced platelet activation and enhancing thrombin- and collagen-induced platelet activation. GPIb-IX signaling requires SFK (Src family kinase) Lyn. However, it remains unclear how Lyn mediates GPIb-IX signaling, whether Lyn directly binds to GPIb-IX, and if it is possible to target this signaling node for developing novel antithrombotics.METHODS AND RESULTSLyn directly binds to GPIb (glycoprotein Ib) β subunit between amino acids 144 to 161 at the transmembrane/cytoplasmic domain interface, and this binding is critical for not only the extracellular GPIb-IX ligand-induced intracellular signaling but also transmits outbound signals enhancing VWF-GPIb-IX interaction. A small peptide, mPLβ, derived from the Lyn binding site in GPIbβ, inhibited VWF-induced or α-thrombin-induced GPIbβ-Lyn interaction, Lyn/SFK activation, stable platelet adhesion and aggregation, and, notably, reduced GPIb-mediated platelet adhesion to VWF even in the presence of integrin inhibitors. Biomembrane force probe study further shows that mPLβ reduces the VWF-A1 domain-GPIb adhesion frequency and inhibits force-induced A1-mediated intraplatelet calcium elevation. Importantly, mPLβ formulated as a high-loading peptide nanoparticle inhibited platelet adhesion/aggregation induced by collagen and in vivo arterial thrombosis with a mild effect in prolonging bleeding time.CONCLUSIONSDirect binding of Lyn to GPIbβ mediates 2-way GPIb-IX signaling to activate platelets and modulate VWF-GPIb interaction. Lyn-mediated GPIb-IX signaling is critical for platelet adhesion and aggregation induced by VWF and collagen and in arterial thrombosis. Targeting the Lyn-GPIbβ interaction, thus, has the potential for treating GPIb-IX-dependent thrombosis.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"90 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145440637","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}
Pub Date : 2025-11-04DOI: 10.1161/circresaha.125.326839
Aarushi Singhal,Stefan Russo,Umesh Kumar Dhawan,Kunzangla Bhutia,Christopher G Bell,Hedayatullah Hayat,Thomas D Nightingale,Monica de Gaetano,Orina Belton,Eoin Brennan,Patricia B Munroe,Catherine Godson,Mary Barry,Carol C Shoulders,Heather L Wilson,Guillermo Velasco,Endre Kiss-Toth,Manikandan Subramanian
BACKGROUNDDefective macrophage efferocytosis is a key driver of chronic nonresolving inflammation in dyslipidemia-associated diseases, such as obesity and atherosclerosis. However, the mechanism by which intracellular lipid accumulation impairs macrophage efferocytosis remains unclear. We hypothesized that lipid-induced endoplasmic reticulum (ER) stress mediates defective macrophage efferocytosis.METHODSBone marrow-derived macrophages were exposed to 7-ketocholesterol or palmitate to induce ER stress, and efferocytosis was quantified by measuring uptake of fluorescently labeled apoptotic cells with microscopy and flow cytometry. Key pathways were interrogated with pharmacological inhibitors, siRNA, and in vivo models, including obese mice and in Ldlr-/- mice with hematopoietic-specific deletion of TRIB3 (Tribbles pseudokinase-3). Human relevance was assessed by testing efferocytosis in macrophages from individuals carrying the TRIB3 Q84R coronary artery disease risk variant (rs2295490) and by examining carotid endarterectomy samples.RESULTSActivation of the ATF4 (activating transcription factor 4) branch of the ER stress pathway in lipid-loaded foamy macrophages led to upregulation of TRIB3, which triggered the downregulation of Rab27a, resulting in impaired focal exocytosis of intracellular membrane pools towards nascent, apoptotic cell-containing phagosomes. The resultant delay in phagosome closure stalled efferocytosis. In obese mice, this impairment was reversed using an ER stress-relieving chemical chaperone and via macrophage-specific knockdown of ATF4 or TRIB3. In atherosclerotic mice, hematopoietic cell-specific deletion of TRIB3 led to increased lesional efferocytosis, decreased plaque necrosis, and increased collagen, which are characteristic of stable plaques. In humans, TRIB3 expression was higher in vulnerable regions of carotid plaques, and macrophages from individuals carrying the gain-of-function TRIB3 Q84R risk variant expressed more TRIB3 and displayed decreased efferocytosis.CONCLUSIONSLipid-induced ER stress impairs macrophage efferocytosis via activation of the ATF4-TRIB3-Rab27a signaling axis, leading to exacerbated plaque necrosis. Targeted disruption of TRIB3 signaling in macrophages represents a novel therapeutic approach to promote efferocytosis and stabilize atherosclerotic plaques.
{"title":"TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis.","authors":"Aarushi Singhal,Stefan Russo,Umesh Kumar Dhawan,Kunzangla Bhutia,Christopher G Bell,Hedayatullah Hayat,Thomas D Nightingale,Monica de Gaetano,Orina Belton,Eoin Brennan,Patricia B Munroe,Catherine Godson,Mary Barry,Carol C Shoulders,Heather L Wilson,Guillermo Velasco,Endre Kiss-Toth,Manikandan Subramanian","doi":"10.1161/circresaha.125.326839","DOIUrl":"https://doi.org/10.1161/circresaha.125.326839","url":null,"abstract":"BACKGROUNDDefective macrophage efferocytosis is a key driver of chronic nonresolving inflammation in dyslipidemia-associated diseases, such as obesity and atherosclerosis. However, the mechanism by which intracellular lipid accumulation impairs macrophage efferocytosis remains unclear. We hypothesized that lipid-induced endoplasmic reticulum (ER) stress mediates defective macrophage efferocytosis.METHODSBone marrow-derived macrophages were exposed to 7-ketocholesterol or palmitate to induce ER stress, and efferocytosis was quantified by measuring uptake of fluorescently labeled apoptotic cells with microscopy and flow cytometry. Key pathways were interrogated with pharmacological inhibitors, siRNA, and in vivo models, including obese mice and in Ldlr-/- mice with hematopoietic-specific deletion of TRIB3 (Tribbles pseudokinase-3). Human relevance was assessed by testing efferocytosis in macrophages from individuals carrying the TRIB3 Q84R coronary artery disease risk variant (rs2295490) and by examining carotid endarterectomy samples.RESULTSActivation of the ATF4 (activating transcription factor 4) branch of the ER stress pathway in lipid-loaded foamy macrophages led to upregulation of TRIB3, which triggered the downregulation of Rab27a, resulting in impaired focal exocytosis of intracellular membrane pools towards nascent, apoptotic cell-containing phagosomes. The resultant delay in phagosome closure stalled efferocytosis. In obese mice, this impairment was reversed using an ER stress-relieving chemical chaperone and via macrophage-specific knockdown of ATF4 or TRIB3. In atherosclerotic mice, hematopoietic cell-specific deletion of TRIB3 led to increased lesional efferocytosis, decreased plaque necrosis, and increased collagen, which are characteristic of stable plaques. In humans, TRIB3 expression was higher in vulnerable regions of carotid plaques, and macrophages from individuals carrying the gain-of-function TRIB3 Q84R risk variant expressed more TRIB3 and displayed decreased efferocytosis.CONCLUSIONSLipid-induced ER stress impairs macrophage efferocytosis via activation of the ATF4-TRIB3-Rab27a signaling axis, leading to exacerbated plaque necrosis. Targeted disruption of TRIB3 signaling in macrophages represents a novel therapeutic approach to promote efferocytosis and stabilize atherosclerotic plaques.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"128 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433893","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}
Pub Date : 2025-10-27DOI: 10.1161/circresaha.125.326701
Kim Jürgen Krott,Tobias Feige,Agnes Bosbach,Alicia Noeme Beele,Irena Krüger,Friedrich Reusswig,Elena Schickentanz-Dey,Susanne Pfeiler,Alexandra Chadt,Malte Kelm,Norbert Gerdes,Kerstin Jurk,Klytaimnistra Kiouptsi,Christoph Reinhardt,Hadi Al-Hasani,Beate E Kehrel,Saoussen Karray,Madhumita Chatterjee,Hubert Schelzig,Markus Udo Wagenhäuser,Margitta Elvers
BACKGROUNDRed blood cells (RBCs) contribute to hemostasis and thrombosis by interacting with platelets via the FasL-FasR pathway to induce procoagulant activity and thrombin formation. Here, we identified a novel mechanism of platelet-RBC interaction via the CD36-TSP-1 (thrombospondin-1) signaling pathway that plays a prominent role in arterial thrombosis and abdominal aortic aneurysm (AAA) formation and progression. AAA is a life-threatening atherosclerotic-related disease, characterized by the progressive dilation of the abdominal aorta, due to chronic inflammation and extracellular matrix remodeling/degradation within the vessel wall. The objective of the present study was to elucidate a new mechanism of platelet-RBC interaction via the TSP1-CD36 axis and its significance for arterial thrombosis and the pathology of AAA.METHODSTSP-1-deficient and CD36 cell-type-specific (RBCs and platelets) knock-out mice were analyzed in experimental mouse models of arterial thrombosis and AAA. Blood samples from patients with AAA from peripheral sites (laminar flow) and from inside the aneurysm segment (turbulent flow) were analyzed by flow cytometry and compared with age-matched controls.RESULTSAfter platelet activation, platelet-released TSP-1 binds to CD36 at the RBC and platelet membrane to enhance procoagulant activity of both cells, leading to platelet aggregation and thrombosis. Patients with AAA exhibit enhanced procoagulant activity, elevated TSP-1 and CD36 plasma levels, as well as increased exposure of TSP-1 and CD36 at the RBC and platelet surface. In addition, biomechanically stress in the aneurysmal segment reinforces CD36 externalization on RBCs and platelets as well as the formation of platelet-RBC aggregates. In line, genetic deletion of either CD36 (RBC restricted) or TSP-1 protected mice against experimentally induced AAA formation.CONCLUSIONSOur findings imply that CD36 on RBCs and platelets, as well as platelet-released TSP-1, contribute to procoagulant activity, playing a crucial role in arterial thrombosis and AAA progression.
{"title":"Interplay Between Thrombospondin-1 and CD36 Modulates Platelet-RBC Interaction in Thrombosis and Abdominal Aneurysm Formation.","authors":"Kim Jürgen Krott,Tobias Feige,Agnes Bosbach,Alicia Noeme Beele,Irena Krüger,Friedrich Reusswig,Elena Schickentanz-Dey,Susanne Pfeiler,Alexandra Chadt,Malte Kelm,Norbert Gerdes,Kerstin Jurk,Klytaimnistra Kiouptsi,Christoph Reinhardt,Hadi Al-Hasani,Beate E Kehrel,Saoussen Karray,Madhumita Chatterjee,Hubert Schelzig,Markus Udo Wagenhäuser,Margitta Elvers","doi":"10.1161/circresaha.125.326701","DOIUrl":"https://doi.org/10.1161/circresaha.125.326701","url":null,"abstract":"BACKGROUNDRed blood cells (RBCs) contribute to hemostasis and thrombosis by interacting with platelets via the FasL-FasR pathway to induce procoagulant activity and thrombin formation. Here, we identified a novel mechanism of platelet-RBC interaction via the CD36-TSP-1 (thrombospondin-1) signaling pathway that plays a prominent role in arterial thrombosis and abdominal aortic aneurysm (AAA) formation and progression. AAA is a life-threatening atherosclerotic-related disease, characterized by the progressive dilation of the abdominal aorta, due to chronic inflammation and extracellular matrix remodeling/degradation within the vessel wall. The objective of the present study was to elucidate a new mechanism of platelet-RBC interaction via the TSP1-CD36 axis and its significance for arterial thrombosis and the pathology of AAA.METHODSTSP-1-deficient and CD36 cell-type-specific (RBCs and platelets) knock-out mice were analyzed in experimental mouse models of arterial thrombosis and AAA. Blood samples from patients with AAA from peripheral sites (laminar flow) and from inside the aneurysm segment (turbulent flow) were analyzed by flow cytometry and compared with age-matched controls.RESULTSAfter platelet activation, platelet-released TSP-1 binds to CD36 at the RBC and platelet membrane to enhance procoagulant activity of both cells, leading to platelet aggregation and thrombosis. Patients with AAA exhibit enhanced procoagulant activity, elevated TSP-1 and CD36 plasma levels, as well as increased exposure of TSP-1 and CD36 at the RBC and platelet surface. In addition, biomechanically stress in the aneurysmal segment reinforces CD36 externalization on RBCs and platelets as well as the formation of platelet-RBC aggregates. In line, genetic deletion of either CD36 (RBC restricted) or TSP-1 protected mice against experimentally induced AAA formation.CONCLUSIONSOur findings imply that CD36 on RBCs and platelets, as well as platelet-released TSP-1, contribute to procoagulant activity, playing a crucial role in arterial thrombosis and AAA progression.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"59 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370623","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}
Pub Date : 2025-10-24Epub Date: 2025-10-23DOI: 10.1161/RES.0000000000000735
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000735","DOIUrl":"https://doi.org/10.1161/RES.0000000000000735","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 10","pages":"1229-1230"},"PeriodicalIF":16.2,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354040","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}
Pub Date : 2025-10-23DOI: 10.1161/circresaha.125.326841
Shanna Hamilton,Radmila Terentyeva,Roland Veress,Fruzsina Perger,Zuzana Nichtova,Mark Bannister,Jinxi Wang,Sage Quiggle,Rachel Battershell,Matthew W Gorr,Sandor Györke,Bum-Rak Choi,Christopher H George,Andriy E Belevych,György Csordás,Dmitry Terentyev
BACKGROUNDMitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increases [Ca2+] in the mitochondrial intermembrane space (IMS) and activates the Ca2+-sensitive protease calpain, driving remodeling of mitochondrial cristae architecture through cleavage of structural protein OPA1 (optic atrophy protein 1).METHODSWe generated a highly arrhythmogenic rat model of catecholaminergic polymorphic ventricular tachycardia, induced by RyR2 gain-of-function mutation S2236L(±). We created a new biosensor to measure IMS-[Ca2+] in adult cardiomyocytes with intact Ca2+ cycling. We used ex vivo whole heart optical mapping, confocal and electron microscopy, as well as in vivo/in vitro gene editing techniques to test the effects of calpain in the IMS.RESULTSWe found altered mitochondrial cristae structure, increased IMS-[Ca2+], reduced OPA1 expression, and augmented mito-reactive oxygen species emission in catecholaminergic polymorphic ventricular tachycardia myocytes. We show that calpain-mediated OPA1 cleavage led to disrupted cristae organization and, thereby, decreased electron transport chain supercomplex assembly, resulting in accelerated reactive oxygen species production. Genetic inhibition of calpain activity in IMS reversed mitochondria structural defects in catecholaminergic polymorphic ventricular tachycardia myocytes and reduced arrhythmic burden in ex vivo optically mapped hearts.CONCLUSIONSOur data suggest that RyR2 hyperactivity contributes to mitochondrial structural damage by promoting an increase in IMS-[Ca2+], sufficient to activate IMS-residing calpain. Calpain activation leads to proteolysis of OPA1 and cristae widening, thereby decreasing assembly of electron transport chain components into supercomplexes. Consequently, excessive mito-reactive oxygen species release critically contributes to RyR2 hyperactivation and ventricular tachyarrhythmia. Our new findings suggest that targeting IMS calpain may be beneficial in patients at risk for sudden cardiac death.
{"title":"Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT.","authors":"Shanna Hamilton,Radmila Terentyeva,Roland Veress,Fruzsina Perger,Zuzana Nichtova,Mark Bannister,Jinxi Wang,Sage Quiggle,Rachel Battershell,Matthew W Gorr,Sandor Györke,Bum-Rak Choi,Christopher H George,Andriy E Belevych,György Csordás,Dmitry Terentyev","doi":"10.1161/circresaha.125.326841","DOIUrl":"https://doi.org/10.1161/circresaha.125.326841","url":null,"abstract":"BACKGROUNDMitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increases [Ca2+] in the mitochondrial intermembrane space (IMS) and activates the Ca2+-sensitive protease calpain, driving remodeling of mitochondrial cristae architecture through cleavage of structural protein OPA1 (optic atrophy protein 1).METHODSWe generated a highly arrhythmogenic rat model of catecholaminergic polymorphic ventricular tachycardia, induced by RyR2 gain-of-function mutation S2236L(±). We created a new biosensor to measure IMS-[Ca2+] in adult cardiomyocytes with intact Ca2+ cycling. We used ex vivo whole heart optical mapping, confocal and electron microscopy, as well as in vivo/in vitro gene editing techniques to test the effects of calpain in the IMS.RESULTSWe found altered mitochondrial cristae structure, increased IMS-[Ca2+], reduced OPA1 expression, and augmented mito-reactive oxygen species emission in catecholaminergic polymorphic ventricular tachycardia myocytes. We show that calpain-mediated OPA1 cleavage led to disrupted cristae organization and, thereby, decreased electron transport chain supercomplex assembly, resulting in accelerated reactive oxygen species production. Genetic inhibition of calpain activity in IMS reversed mitochondria structural defects in catecholaminergic polymorphic ventricular tachycardia myocytes and reduced arrhythmic burden in ex vivo optically mapped hearts.CONCLUSIONSOur data suggest that RyR2 hyperactivity contributes to mitochondrial structural damage by promoting an increase in IMS-[Ca2+], sufficient to activate IMS-residing calpain. Calpain activation leads to proteolysis of OPA1 and cristae widening, thereby decreasing assembly of electron transport chain components into supercomplexes. Consequently, excessive mito-reactive oxygen species release critically contributes to RyR2 hyperactivation and ventricular tachyarrhythmia. Our new findings suggest that targeting IMS calpain may be beneficial in patients at risk for sudden cardiac death.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"93 1 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339413","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}
Pub Date : 2025-10-23DOI: 10.1161/circresaha.125.327423
Ilana S Nazari,Edward B Thorp,Matthew J Feinstein
{"title":"Ensnarement of Stressed Macrophages by NETs in Atherosclerosis.","authors":"Ilana S Nazari,Edward B Thorp,Matthew J Feinstein","doi":"10.1161/circresaha.125.327423","DOIUrl":"https://doi.org/10.1161/circresaha.125.327423","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"20 1","pages":"1276-1278"},"PeriodicalIF":20.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351601","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}
Pub Date : 2025-10-23DOI: 10.1161/circresaha.124.326070
Nobuaki Fukuma,Christos Tzimas,Ilaria Russo,Wen Dun,Michelle L Lance,Yi Zhang,Jared S Kushner,Charles W Emala,Andreas Friebe,Nathan R Tucker,Emily J Tsai
BACKGROUNDRight ventricular (RV) dysfunction increases mortality in heart failure and pulmonary hypertension. However, women demonstrate better RV function and survival than men. This difference is attributed to estrogen, though mechanistic details remain unclear. Given estrogen's stimulation of NO production, we investigated whether and how cardiomyocyte NO-sensitive soluble GC1 (guanylyl cyclase) mediates female-specific, adaptive RV pressure-overload remodeling.METHODSAdult male and female mice with cardiomyocyte-specific GC1 deficiency (cardiomyocyte-specific knockout) and littermate controls underwent pulmonary artery banding (PAB) or thoracotomy (Sham). At 6-week postsurgery, RV function was assessed via echocardiography, pressure-volume loops, and treadmill testing. RV function, histopathology, and transcript profiles were compared across sex, genotype, and surgical group. Single-nucleus RNA sequencing of RV tissue was performed to identify putative cardiomyocyte GC1-mediated cell-cell communication in adaptive RV pressure-overload remodeling. Endothelial coculture assays with controls versus cardiomyocyte-specific knockout cardiomyocytes evaluated estrogen and cardiomyocyte GC1-dependence of the identified intercellular signaling.RESULTSFemale controls PAB adapted RV contractility to overcome RV pressure-overload, thereby preserving RV-PA coupling. In contrast, female cardiomyocyte-specific knockout, ovariectomized female controls, and male PAB developed severe RV dysfunction with RV-PA uncoupling. These groups with maladapted RVs had marked cardiomyocyte hypertrophy, interstitial fibrosis, and capillary rarefaction; female control PAB had minimal changes. Among histological features, the capillary-to-cardiomyocyte ratio showed the strongest correlation with RV function. Ratios were similar between female control PAB and Sham, but abnormally low in all other PAB. Single-nucleus RNA sequence and coculture analyses revealed that cardiomyocyte GC1 is central to Vegf (vascular endothelial growth factor)-Vegfr proangiogenic signaling from cardiomyocytes to endothelial cells in the adaptively remodeled, pressure-overloaded RV.CONCLUSIONSWe identified a novel estrogen- and cardiomyocyte GC1-dependent pathway that mitigates capillary rarefaction, maintaining normal capillary-to-cardiomyocyte ratio and preserving RV-PA coupling under RV pressure-overload. This proangiogenic, estrogen- and cardiomyocyte GC1-dependent mechanism contributes to sex-specific differences in RV remodeling and may inform the development of targeted therapies for RV dysfunction.
{"title":"Cardiomyocyte GC1 Mediates Estrogenic Angiogenesis in Right Heart Remodeling.","authors":"Nobuaki Fukuma,Christos Tzimas,Ilaria Russo,Wen Dun,Michelle L Lance,Yi Zhang,Jared S Kushner,Charles W Emala,Andreas Friebe,Nathan R Tucker,Emily J Tsai","doi":"10.1161/circresaha.124.326070","DOIUrl":"https://doi.org/10.1161/circresaha.124.326070","url":null,"abstract":"BACKGROUNDRight ventricular (RV) dysfunction increases mortality in heart failure and pulmonary hypertension. However, women demonstrate better RV function and survival than men. This difference is attributed to estrogen, though mechanistic details remain unclear. Given estrogen's stimulation of NO production, we investigated whether and how cardiomyocyte NO-sensitive soluble GC1 (guanylyl cyclase) mediates female-specific, adaptive RV pressure-overload remodeling.METHODSAdult male and female mice with cardiomyocyte-specific GC1 deficiency (cardiomyocyte-specific knockout) and littermate controls underwent pulmonary artery banding (PAB) or thoracotomy (Sham). At 6-week postsurgery, RV function was assessed via echocardiography, pressure-volume loops, and treadmill testing. RV function, histopathology, and transcript profiles were compared across sex, genotype, and surgical group. Single-nucleus RNA sequencing of RV tissue was performed to identify putative cardiomyocyte GC1-mediated cell-cell communication in adaptive RV pressure-overload remodeling. Endothelial coculture assays with controls versus cardiomyocyte-specific knockout cardiomyocytes evaluated estrogen and cardiomyocyte GC1-dependence of the identified intercellular signaling.RESULTSFemale controls PAB adapted RV contractility to overcome RV pressure-overload, thereby preserving RV-PA coupling. In contrast, female cardiomyocyte-specific knockout, ovariectomized female controls, and male PAB developed severe RV dysfunction with RV-PA uncoupling. These groups with maladapted RVs had marked cardiomyocyte hypertrophy, interstitial fibrosis, and capillary rarefaction; female control PAB had minimal changes. Among histological features, the capillary-to-cardiomyocyte ratio showed the strongest correlation with RV function. Ratios were similar between female control PAB and Sham, but abnormally low in all other PAB. Single-nucleus RNA sequence and coculture analyses revealed that cardiomyocyte GC1 is central to Vegf (vascular endothelial growth factor)-Vegfr proangiogenic signaling from cardiomyocytes to endothelial cells in the adaptively remodeled, pressure-overloaded RV.CONCLUSIONSWe identified a novel estrogen- and cardiomyocyte GC1-dependent pathway that mitigates capillary rarefaction, maintaining normal capillary-to-cardiomyocyte ratio and preserving RV-PA coupling under RV pressure-overload. This proangiogenic, estrogen- and cardiomyocyte GC1-dependent mechanism contributes to sex-specific differences in RV remodeling and may inform the development of targeted therapies for RV dysfunction.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"51 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339412","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}
Pub Date : 2025-10-23DOI: 10.1161/circresaha.125.327424
Yann Grobs,Francois Potus
{"title":"GP130 in Right Ventricular Dysfunction: Omics and Pig Insights.","authors":"Yann Grobs,Francois Potus","doi":"10.1161/circresaha.125.327424","DOIUrl":"https://doi.org/10.1161/circresaha.125.327424","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"45 1","pages":"1252-1254"},"PeriodicalIF":20.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351599","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}
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