Basic Research in Cardiology最新文献

{"title":"Potassium as an electro-metabolic signal for local coronary vasodilation.","authors":"Johnathan D Tune,Dirk J Duncker,Adam G Goodwill,Cooper M Warne,Salman I Essajee,Selina M Tucker,Steven A Romero,Shawn B Bender,Daniel A Beard,C Alberto Figueroa,Oana Sorop,Daphne Merkus,Gregory M Dick","doi":"10.1007/s00395-025-01126-9","DOIUrl":"https://doi.org/10.1007/s00395-025-01126-9","url":null,"abstract":"This study tested the hypothesis that K+ serves as an in vivo signal coupling coronary blood flow with the oxidative requirements of the myocardium. Experiments were performed in swine in which coronary parameters and arterial and coronary venous [K+] were measured under baseline conditions, during exogenous administration of K+ (1-5 mM; n = 4), during increases in myocardial oxygen consumption (MVO2) to dobutamine (n = 7) and exercise (n = 6), alterations in coronary perfusion pressure (CPP; n = 8), and systemic hypoxemia (PaO2 to ~ 30 mmHg; n = 7). Exogenous intracoronary K+ increased blood flow (~ 20%) in direct proportion to the coronary venous [K+] up to the lethal limit of ~ 10 mM. Dobutamine increased coronary flow and MVO2 ~ threefold but the coronary venous-arterial [K+] gradient (i.e., a surrogate index of myocardial release of K+ into the coronary circulation) did not change. Similarly, exercise increased coronary flow and MVO2 ~ 2.5-fold without a change in the coronary venous-arterial [K+] gradient. The coronary venous-arterial [K+] gradient did not change over the CPP range of 140-40 mmHg. Hypoxemia increased coronary blood flow ~ twofold and coronary vascular resistance was weakly associated with < 0.5 mM change in the coronary venous-arterial [K+] gradient. Intracoronary glibenclamide dose-dependently (1-3 mg/min; n = 4) increased coronary resistance but did not affect the coronary venous-arterial [K+] gradient. Intracoronary pinacidil dose-dependently (0.3-3.0 µg/kg/min; n = 3) increased coronary blood flow but did not affect the coronary venous-arterial [K+] gradient. Similarly, intravenous glibenclamide (3 mg/kg; n = 6) increased coronary resistance but did not affect the coronary venous-arterial [K+] gradient in exercising swine. These findings fail to support the concept that myocardial interstitial [K+] couples coronary blood flow to MVO2 during physiologic increases in cardiac work or when oxygen delivery is constrained.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"20 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478761","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":"The innate immune receptor NLRX1 is a novel required modulator for mPTP opening: implications for cardioprotection.","authors":"Y Xiao,X Hu,C F Rudolphi,E E Nollet,R Nederlof,Q Wang,D Bakker,Panagiota Efstathia Nikolaou,J C Knol,R R Goeij-de Haas,A A Henneman,T V Pham,C R Jimenez,A E Grootemaat,N N van der Wel,S E Girardin,N Kaludercic,J van der Velden,Z Onódi,P Leszek,Z V Varga,P Ferdinandy,B Preckel,N C Weber,M W Hollmann,F Di Lisa,C J Zuurbier","doi":"10.1007/s00395-025-01124-x","DOIUrl":"https://doi.org/10.1007/s00395-025-01124-x","url":null,"abstract":"NLRX1 is the only NOD-like innate immune receptor that localises to mitochondria. We previously demonstrated that NLRX1 deletion increased infarct size in isolated mouse hearts subjected to ischemia-reperfusion injury (IRI); however, underlying mechanisms are yet to be identified. Given the crucial role played by mitochondria in cardiac IRI, we here hypothesise that NLRX1 affects key mechanisms of cardiac IRI. Cardiac IRI was evaluated in isolated C57BL/6J (WT) and NLRX1 knock out (KO) mouse hearts. The following known modulators of IRI were explored in isolated hearts, isolated mitochondria; or permeabilised cardiac fibres: 1) mTOR/RISK/autophagy regulation, 2) AMPK and mitochondrial energy production, and 3) mitochondrial permeability transition pore (mPTP) opening. NLRX1 deletion increased IRI, and cardiac NLRX1 was decreased after IRI in mouse and pig hearts. NLRX1 ablation caused decreased mTOR and RISK pathway (Akt, ERK, and S6K) activation following IR, without affecting autophagy/inflammation/oxidative stress markers. The RISK activator Urocortin dissipated NLRX1 effects on mTOR, RISK pathway and IRI, indicating that increased cardiac IRI with NLRX1 deletion is, at least partly, due to impaired RISK activation. The energy sensor AMPK was activated in NLRX1 KO hearts, possibly due to slowed mitochondrial respiratory responses (impaired mitochondrial permeability) towards palmitoylcarnitine in permeabilised cardiac fibres. NLRX1 deletion completely abolished calcium-induced mPTP opening, and cyclosporine A (CsA) effects on mPTP, both before and after IR, and was associated with increased mitochondrial calcium content after IR. Mitochondrial sub-fractionation studies localised NLRX1 to the inner mitochondrial membrane. NLRX1 deletion associated with decreased phosphorylation of mitochondrial Got2, Cx43, Myl2, Ndufb7 and MICOS10. The mPTP inhibitor CsA abolished IRI differences between KO and WT hearts, suggesting that the permanent closure of mPTP due to NLRX1 deletion contributed to the increased IR sensitivity of NLRX1 KO hearts. This is the first demonstration that the mitochondrial NLRX1 is a novel factor required for mPTP opening and contributes to cardioprotection against acute IRI through RISK pathway activation and prevention of permanent mPTP closure.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"38 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320364","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":"Antimicrobial peptide CRAMP/LL-37 mediates ferroptosis resistance in cardiomyocytes by inhibiting cathepsin L.","authors":"Zhantao Liu,Qingsong Zhang,Dan Su,Hong Chen,Bowen Wang,Lin Ye,Peiyan Wang,Jingnan Wu,Wencan Jia,Lijun Liu,Jianxun Wang,Shuo Miao","doi":"10.1007/s00395-025-01122-z","DOIUrl":"https://doi.org/10.1007/s00395-025-01122-z","url":null,"abstract":"Ferroptosis is an important cause of cardiomyocyte loss and cardiac dysfunction. Cathelicidin-related antimicrobial peptide (CRAMP) is an endogenous polypeptide that regulates oxidative stress in the body and is involved in ferroptosis. However, its specific role and mechanism in ferroptosis are unclear. To analyze the role of CRAMP in ferroptosis, we first analyzed its expression in infarcted myocardial tissues, and verified its role in ferroptosis in vitro through overexpression and knock-down techniques. The activity and expression of cathepsin L (CTSL) and its effect on ferroptosis were analyzed to verify whether CTSL participated in ferroptosis as a downstream of CRAMP. Protein disulfide isomerase family A member 4 (PDIA4) was screened as an interacting protein of CTSL by using the database, and the role of PDIA4 in ferroptosis was analyzed by gene knockdown and overexpression. Finally, the regulatory mechanism of CRAMP in ferroptosis was verified in vivo by mouse myocardial infarction model. CRAMP levels were reduced in both infarcted cardiac tissues and cardiomyocytes exposed to ferroptosis inducers. The overexpression of CRAMP or pretreatment of LL-37 alleviated cardiomyocyte ferroptosis, whereas CRAMP knockdown exacerbated cell death. Under ferroptotic stress, the expression of CTSL was elevated. CRAMP inhibited ferroptosis by antagonizing the CTSL activity. Abnormal increase in CTSL activity and levels caused PDIA4 to decrease. Overexpression of PDIA4 inhibited ferroptosis induced by CTSL, while knocking down PDIA4 counteracted the protection of CRAMP. In vivo, both CRAMP overexpression and administration of CRAMP peptide significantly ameliorated myocardial injury and improved cardiac function. CRAMP increases PDIA4 levels by inhibiting the activity of CTSL and antagonizes ferroptosis in cardiomyocytes. Targeting CRAMP offers innovative therapeutic strategies and insights for the prevention and management of myocardial injury.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"91 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295699","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":"Direction-dependent contributions of cardiac myofilament networks to myocardial passive stiffness reveal a major disparity for titin.","authors":"Felix A Wagner, Christine M Loescher, Andreas Unger, Michel Kühn, Annika J Klotz, Ivan Liashkovich, Dominika Ciechanska, Hermann Schillers, Franziska Koser, Johanna K Freundt, Anthony L Hessel, Wolfgang A Linke","doi":"10.1007/s00395-025-01119-8","DOIUrl":"https://doi.org/10.1007/s00395-025-01119-8","url":null,"abstract":"<p><p>Progressive myocardial dysfunction in patients with heart failure often involves alterations in myocardial passive stiffness, yet the underlying mechanisms remain incompletely understood. While passive stiffness in the longitudinal direction has been extensively characterized via uniaxial tensile stretching of cardiac specimens, transverse stiffness has received far less attention despite its equal mechanical importance. In this study, we combined atomic force microscopy nanoindentation with stretching assays on myocardial preparations to quantify the relative contributions of the three myofilament networks - actin, myosin, and titin - to passive stiffness in both transverse and longitudinal orientations. We employed a transgenic mouse model in which titin's elastic springs contain a tobacco etch virus protease (TEVp) recognition site, enabling selective and acute titin cleavage upon TEVp treatment. Actin filaments were severed using a calcium-independent gelsolin fragment, and myosin filaments were dissociated by high-salt extraction. Along the longitudinal axis, titin accounted for over 50% of total passive stiffness in both cardiac fiber bundles and isolated cardiomyocytes across most physiological strain ranges, whereas actin contributed under 35% overall - and only 15-20% within the collagen-containing fiber bundles. In contrast, in the transverse axis, titin and actin each contributed approximately 20-26% of passive stiffness in cardiac slices under varying compression forces. The myosin-titin composite thick-filament network contributed ~ 55% longitudinally but only ~ 35% transversely. These results reveal pronounced, direction-dependent differences in myofilament contributions to myocardial passive stiffness, with titin exhibiting the greatest disparity. Our findings deepen our understanding of the myocardium's multidimensional mechanics and may inform therapeutic strategies to ameliorate pathological cardiac stiffening.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282309","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":"Molecular screening in a translational large animal trial identifies a differential inflammatory response for MINOCA.","authors":"Jasper Iske, Joshua M Mesfin, Petra Wolint, Miriam Weisskopf, Christien Beez, Henriette Thau, Christian T Stoeck, January M Weiner, Melanie M Hierweger, Eva van Gelder, Thorald Stolte, Nuri Ünesen, Ross Straughan, Lucas S J Eckholt, Nina Trimmel, Dieter Beule, Heike Meyborg, Timo Z Nazari-Shafti, Volkmar Falk, Maximilian Y Emmert, Nikola Cesarovic","doi":"10.1007/s00395-025-01118-9","DOIUrl":"https://doi.org/10.1007/s00395-025-01118-9","url":null,"abstract":"<p><p>Myocardial infarction without obstructive coronary arteries (MINOCA) comprises up to 15% of all myocardial infarctions (MI) and could be caused by cardiac microembolization (CME) originating from plaque rupture and/or erosion. Early diagnosis remains a challenge due to limited early biomarkers, leading to high morbidity. Here, we have systematically characterized acute (up to 5 h) CME-induced MINOCA in comparison to MI using clinical markers, histology, multi-ELISAs, miRNA profiling, and proteomics in a translational porcine animal model. CME-induced MINOCA model was created by injecting autologous microthrombi, generated by carotid crush maneuver, into the coronary arteries, whereas MI was induced by LAD balloon occlusion/reperfusion. MINOCA animals exhibited low troponin (547.0 ± 489.2 ng/L) and creatine kinase (1827.8 ± 677.3 U/L) levels, as well as infarct size (2.3 ± 0.8%), necrosis (7.6 ± 3.2%), and interstitial hemorrhage (0.6 ± 0.4%). Immune cell infiltration surrounding MINOCA microthrombi sites was significantly higher (1532 ± 722 cells/mm²) in comparison to MI infarct zones (470 ± 320 cells/mm²). Furthermore, cytokine profiling showed elevated IL-1α and IL-1β in both groups, higher IL-10 in MINOCA, and higher IFN-y in MI. The MINOCA-specific pro-inflammatory miRNA, ssc-miR-802, was identified. Plasma proteomic analysis revealed leukotriene signaling as a MINOCA inflammatory pathway with augmented leukotriene-A4-hydrolase levels. Its product, leukotriene B4, was increased in MINOCA serum at 150 min (1031 ± 537.6 pg/mL) and 300 min (1309 ± 640.8 pg/mL) and in tissue (408.2 ± 92.12 pg/mL) vs. MI (428.9 ± 9.483 pg/mL in serum at 150 min, 308.76 ± 5.484 pg/mL in serum at 300 min, and 76.22 ± 31.12 pg/mL in tissue). In summary, CME-induced MINOCA elicits a distinct pro-inflammatory leukotriene response compared to MI, presenting a new acute MINOCA diagnostic and therapeutic target.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282310","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":"Anti-inflammatory interventions in coronary artery disease: antipodal responses requiring targeted therapeutic strategies.","authors":"Konstantinos Iliodromitis, Melchior Seyfarth, Zsuzsanna Balogh, Harilaos Bogossian, Efstathios Iliodromitis, Filippos Triposkiadis","doi":"10.1007/s00395-025-01121-0","DOIUrl":"https://doi.org/10.1007/s00395-025-01121-0","url":null,"abstract":"<p><p>Inflammation has a key role in coronary atherosclerotic disease (CAD), as it contributes to the development, progression, instability and rupture of the atherosclerotic plaque. The long-term treatment and continuous suppression of inflammation is a therapeutic goal for patients with increased cardiovascular risk and chronic CAD syndromes. In contrast, in acute myocardial infarction (MI), the presence of inflammation is necessary for smooth healing, tissue neovascularization, and limitation of left ventricular remodeling, rendering a \"controlled amount\" of inflammation desirable in this context. As a result, the use of nonselective, broad-spectrum anti-inflammatory drugs does not offer any beneficial effect and may turn out to be harmful. Nevertheless, the possibility that modification of a usual inflammatory response in MI with selective anti-inflammatory agents cannot be excluded. Conversely, an excessive, uncontrolled, and prolonged inflammatory response after an acute MI may result in extensive irreversible myocardial damage and should be timely recognized and treated, preferably with a selective anti-inflammatory agent. In the present review we highlight the key role of inflammation in chronic and acute CAD, discuss the underlying pathophysiology, and present the results of representative experimental and clinical studies evaluating the pharmaceutical modification of the inflammatory response in this context.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274126","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":"Exploring hiPSC-CM replacement therapy in ischemic hearts.","authors":"Giuseppe Cipriano, Thomas Thum, Natalie Weber","doi":"10.1007/s00395-025-01117-w","DOIUrl":"https://doi.org/10.1007/s00395-025-01117-w","url":null,"abstract":"<p><p>Ischemic heart disease is one of the leading causes of heart failure and death worldwide. The loss of cardiomyocytes following a myocardial infarction drives the remodeling process, which, in most cases, ultimately leads to heart failure. Since the available treatment options only slow down the remodeling process without tackling the causes of heart failure onset (i.e., cardiomyocyte loss and inability of the remaining cardiomyocytes to enter the cell cycle and regenerate the heart), in the last two decades, cardiovascular research focused on finding alternative solutions to regenerate the heart. So far, the investigated approaches include a variety of methods aiming at manipulation of non-coding RNAs, such as long non-coding RNA (lncRNA), circular RNA (circRNA), and microRNA (miRNA), and growth factors to enable the cardiomyocytes to re-enter the cell cycle, direct reprogramming of fibroblasts into cardiomyocytes (CM), and CM replacement therapy, all of them with the main goal to replace the loss of cardiomyocytes and restore the heart function. The development of reprogramming protocols from somatic cells to induced pluripotent stem cells (iPSCs) by Yamanaka and Takahashi, along with advancements in differentiation protocols to generate almost pure populations of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), has fostered optimism in cardiac regenerative medicine. Despite these advancements, critical concerns arose regarding the survival and retention of the engrafted cells, arrhythmogenicity, and immune response. Over time, much effort has been put into enhancing iPSC-CM therapy with different methods, ranging from anti-apoptotic small molecule-based approaches to tissue engineering. In this review, we discuss the evolution of cardiac cell therapy, highlighting recent advancements and the remaining challenges that must be overcome to translate this promising approach into clinical practice.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257223","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":"The contribution of cardiomyocyte hypercontracture to the burden of acute myocardial infarction: an update.","authors":"Nur Liyana Mohammed Yusof, Derek M Yellon, Sean M Davidson","doi":"10.1007/s00395-025-01120-1","DOIUrl":"https://doi.org/10.1007/s00395-025-01120-1","url":null,"abstract":"<p><p>Although reperfusion therapy such as percutaneous coronary intervention and thrombolysis have been implemented in clinical practise as treatments for acute myocardial infarction (AMI) since the 1970s, patients continue to experience high rates of morbidity and mortality. Coronary reperfusion is effective as it limits infarction. However, it induces significant myocardial injury, known as ischaemia-reperfusion (IR) injury. Sustained depletion of cellular adenosine triphosphate (ATP) leading to intracellular calcium (Ca²⁺) overload ultimately lead to cardiomyocyte death during ischaemia. Reperfusion enables resynthesis of ATP, but if this occurs whilst Ca²⁺ remains elevated, it induces excessive cardiomyocyte contracture, known as hypercontracture. Irreversible myocardial injury caused by hypercontracture is often accompanied by histological findings such as wavy myocardial fibres, and more profoundly, contraction band necrosis, identified by the presence of dense eosinophilic bands within the cardiomyocytes. The presence of hypercontracture imposes deleterious effects on both cardiac function and clinical outcomes in individuals experiencing AMI. The potential cardioprotective benefits of inhibiting hypercontracture following IR injury have been demonstrated in animal models, however therapies suitable for clinical application are yet to be developed. This article reviews the pathogenesis and clinical manifestation of hypercontracture in cardiomyocytes during AMI. In addition, the discussion highlights the challenges of translating robust pre-clinical data into successful clinical therapeutic approaches.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246212","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":"Effects of SGLT2 inhibitors on ion channels in heart failure: focus on the endothelium.","authors":"Mengnan Wang,Benedikt Preckel,Coert J Zuurbier,Nina C Weber","doi":"10.1007/s00395-025-01115-y","DOIUrl":"https://doi.org/10.1007/s00395-025-01115-y","url":null,"abstract":"Heart failure (HF) is a life-threatening cardiovascular disease associated with high mortality, diminished quality of life, and a significant economic burden on both patients and society. The pathogenesis of HF is closely related to the endothelium, where endothelial ion channels play an important role in regulating intracellular Ca2+ signals. These ion channels are essential to maintain vascular function, including endothelium-dependent vascular tone, inflammation response, and oxidative stress. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promising cardiovascular benefits in HF patients, reducing mortality risk and hospitalization in several large clinical trials. Clinical and preclinical studies indicate that the cardioprotective effects of SGLT2i in HF are mediated by endothelial nitric oxide (NO) pathways, as well as by reducing inflammation and reactive oxygen species in cardiac endothelial cells. Additionally, SGLT2i may confer endothelial protection by lowering intracellular Ca2+ level through the inhibition of sodium-hydrogen exchanger 1 (NHE1) and sodium-calcium exchanger (NCX) in endothelial cells. In this review, we discuss present knowledge regarding the expression and role of Ca2+-related ion channels in endothelial cells in HF, focusing on the effects of SGLT2i on endothelial NHE1, NCX as well as on vascular tone.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"25 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945457","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":"CD163+ macrophages attenuate pressure overload-induced left ventricular systolic dysfunction and cardiac mitochondrial dysfunction via interleukin-10","authors":"Wei Ni, Xiaofeng Ge, Yang Liu, Jingyu Chen, Lin Wang, Linjian Chen, Zhaokai Li, Peng Zhang, Shufen Huang, Junhui Xu, Le Zhang, Xiabin Fan, Gang Wang, Wei Huang, Yuanchao Ye, Jiancang Zhou, Cuilian Dai, Binbin Liu","doi":"10.1007/s00395-025-01114-z","DOIUrl":"https://doi.org/10.1007/s00395-025-01114-z","url":null,"abstract":"<p>Macrophage depletion exacerbates pressure overload-induced heart failure, but therapeutic translation is hindered by macrophage subset heterogeneity. The functional role of CD163⁺ macrophages in heart failure remains unclear. Transverse aortic constriction (TAC) was employed to induce pressure overload. <i>Cd163</i>^−/− mice exhibited significantly aggravated TAC-induced left ventricular systolic dysfunction, as demonstrated by reduced ejection fraction, fractional shortening, and global longitudinal strain, compared to wild-type (WT) controls. RNA sequencing of cardiac tissues revealed significant differential gene expression between TAC-treated WT and <i>Cd163</i>^−/− mice, especially in pathways governing mitochondrial bioenergetics and homeostasis. Transmission electron microscopy confirmed greater accumulation of dysfunctional mitochondria in cardiomyocytes of <i>Cd163</i>^−/− mice relative to WT following TAC. Additionally, the proportion of CD163⁺ macrophages among cardiac macrophages increased post-TAC. Serum IL-10 levels and cardiac macrophage IL-10 expression were significantly diminished in <i>Cd163</i>^−/− mice compared to WT after TAC. IL-10 supplementation effectively reversed the TAC-induced impairment in left ventricular systolic function in both WT and <i>Cd163</i>^−/− mice, and reduced NADH/NAD⁺ ratios, reduced mitochondrial dysfunction, and improved mitochondrial membrane potential in <i>Cd163</i>^−/− mice. Cross-sectional clinical data supported these findings, showing decreased IL-10 levels as a significant risk factor for heart failure in hypertensive patients (odds ratio: 0.397; 95% CI 0.203–0.775; p = 0.007). Collectively, these results highlight the protective role of CD163⁺ macrophages against pressure overload-induced left ventricular dysfunction and mitochondrial dysfunction through IL-10-dependent pathways.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"75 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926602","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}