Basic Research in Cardiology最新文献

{"title":"Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy.","authors":"Felix Sebastian Nettersheim, Johannes David Schlüter, Wiebke Kreuzberg, Dennis Mehrkens, Simon Grimm, Harshal Nemade, Simon Braumann, Alexander Hof, Henning Guthoff, Vera Peters, Friedrich Felix Hoyer, Yulia Kargapolova, Jan-Wilm Lackmann, Stefan Müller, Christian P Pallasch, Michael Hallek, Agapios Sachinidis, Matti Adam, Holger Winkels, Stephan Baldus, Simon Geißen, Martin Mollenhauer","doi":"10.1007/s00395-023-01006-0","DOIUrl":"10.1007/s00395-023-01006-0","url":null,"abstract":"<p><p>Cardiotoxicity is a major complication of anthracycline therapy that negatively impacts prognosis. Effective pharmacotherapies for prevention of anthracycline-induced cardiomyopathy (AICM) are currently lacking. Increased plasma levels of the neutrophil-derived enzyme myeloperoxidase (MPO) predict occurrence of AICM in humans. We hypothesized that MPO release causally contributes to AICM. Mice intravenously injected with the anthracycline doxorubicin (DOX) exhibited higher neutrophil counts and MPO levels in the circulation and cardiac tissue compared to saline (NaCl)-treated controls. Neutrophil-like HL-60 cells exhibited increased MPO release upon exposition to DOX. DOX induced extensive nitrosative stress in cardiac tissue alongside with increased carbonylation of sarcomeric proteins in wildtype but not in Mpo^-/- mice. Accordingly, co-treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with DOX and MPO aggravated loss of hiPSC-CM-contractility compared to DOX treatment alone. DOX-treated animals exhibited pronounced cardiac apoptosis and inflammation, which was attenuated in MPO-deficient animals. Finally, genetic MPO deficiency and pharmacological MPO inhibition protected mice from the development of AICM. The anticancer efficacy of DOX was unaffected by MPO deficiency. Herein we identify MPO as a critical mediator of AICM. We demonstrate that DOX induces cardiac neutrophil infiltration and release of MPO, which directly impairs cardiac contractility through promoting oxidation of sarcomeric proteins, cardiac inflammation and cardiomyocyte apoptosis. MPO thus emerges as a promising pharmacological target for prevention of AICM.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"36"},"PeriodicalIF":9.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10151445","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":"Identification of the specific molecular and functional signatures of pre-beta-HDL: relevance to cardiovascular disease.","authors":"Isabelle Guillas, Marie Lhomme, Cédric Pionneau, Lucrèce Matheron, Maharajah Ponnaiah, Sophie Galier, Sandrine Lebreton, Marie Delbos, Feng Ma, Maryam Darabi, Petra El Khoury, Marianne Abifadel, Philippe Couvert, Philippe Giral, Philippe Lesnik, Maryse Guerin, Wilfried Le Goff, Anatol Kontush","doi":"10.1007/s00395-023-01004-2","DOIUrl":"10.1007/s00395-023-01004-2","url":null,"abstract":"<p><p>While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"33"},"PeriodicalIF":9.5,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10162496","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":"Preventing mitochondrial reverse electron transport as a strategy for cardioprotection.","authors":"Hiran A Prag, Michael P Murphy, Thomas Krieg","doi":"10.1007/s00395-023-01002-4","DOIUrl":"10.1007/s00395-023-01002-4","url":null,"abstract":"<p><p>In the context of myocardial infarction, the burst of superoxide generated by reverse electron transport (RET) at complex I in mitochondria is a crucial trigger for damage during ischaemia/reperfusion (I/R) injury. Here we outline the necessary conditions for superoxide production by RET at complex I and how it can occur during reperfusion. In addition, we explore various pathways that are implicated in generating the conditions for RET to occur and suggest potential therapeutic strategies to target RET, aiming to achieve cardioprotection.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"34"},"PeriodicalIF":9.5,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10162498","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":"Perspective: mitochondrial STAT3 in cardioprotection.","authors":"Petra Kleinbongard","doi":"10.1007/s00395-023-01003-3","DOIUrl":"10.1007/s00395-023-01003-3","url":null,"abstract":"<p><p>Activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key cardioprotective signal not only in animal studies but also in humans-in animals, STAT3 is causally involved in cardioprotection. In response to late ischemic conditioning, canonical function of STAT3 activation upregulates the expression of cardioprotective and anti-apoptotic proteins. In its non-canonical function, STAT3 is activated during ischemic conditioning and is part of the cardioprotective cytosolic survival activating factor enhancement pathway. Activated STAT3 is imported and localized to the mitochondria. Mitochondrial STAT3 stimulates the activity of mitochondrial electron transport chain complex I, reduces mitochondrial reactive oxygen species production and mitochondrial permeability transition pore opening. Finally, two novel aspects of STAT activation in cardioprotection are discussed: a genetic variance of the STAT encoding region as a potential primordial confounding variable for cardioprotection, and the cardioprotective potential of sodium-glucose cotransporter 2 inhibitors through STAT3 activation.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"32"},"PeriodicalIF":9.5,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10449977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10532278","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":"Rivaroxaban attenuates neutrophil maturation in the bone marrow niche.","authors":"R Schneckmann, M Döring, S Gerfer, S Gorressen, S Heitmeier, C Helten, A Polzin, C Jung, M Kelm, A C Fender, U Flögel, M Grandoch","doi":"10.1007/s00395-023-01001-5","DOIUrl":"10.1007/s00395-023-01001-5","url":null,"abstract":"<p><p>Pharmacological inhibition of factor Xa by rivaroxaban has been shown to mediate cardioprotection and is frequently used in patients with, e.g., atrial fibrillation. Rivaroxaban's anti-inflammatory actions are well known, but the underlying mechanisms are still incompletely understood. To date, no study has focused on the effects of rivaroxaban on the bone marrow (BM), despite growing evidence that the BM and its activation are of major importance in the development/progression of cardiovascular disease. Thus, we examined the impact of rivaroxaban on BM composition under homeostatic conditions and in response to a major cardiovascular event. Rivaroxaban treatment of mice for 7 days markedly diminished mature leukocytes in the BM. While apoptosis of BM-derived mature myeloid leukocytes was unaffected, lineage-negative BM cells exhibited a differentiation arrest at the level of granulocyte-monocyte progenitors, specifically affecting neutrophil maturation via downregulation of the transcription factors Spi1 and Csfr1. To assess whether this persists also in situations of increased leukocyte demand, mice were subjected to cardiac ischemia/reperfusion injury (I/R): 7 d pretreatment with rivaroxaban led to reduced cardiac inflammation 72 h after I/R and lowered circulating leukocyte numbers. However, BM myelopoiesis showed a rescue of the leukocyte differentiation arrest, indicating that rivaroxaban's inhibitory effects are restricted to homeostatic conditions and are mainly abolished during emergency hematopoiesis. In translation, ST-elevation MI patients treated with rivaroxaban also exhibited reduced circulating leukocyte numbers. In conclusion, we demonstrate that rivaroxaban attenuates neutrophil maturation in the BM, which may offer a therapeutic option to limit overshooting of the immune response after I/R.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"31"},"PeriodicalIF":9.5,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10033536","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":"The heterocellular heart: identities, interactions, and implications for cardiology.","authors":"Achim Lother, Peter Kohl","doi":"10.1007/s00395-023-01000-6","DOIUrl":"10.1007/s00395-023-01000-6","url":null,"abstract":"<p><p>The heterocellular nature of the heart has been receiving increasing attention in recent years. In addition to cardiomyocytes as the prototypical cell type of the heart, non-myocytes such as endothelial cells, fibroblasts, or immune cells are coming more into focus. The rise of single-cell sequencing technologies enables  identification of ever more subtle differences and has reignited the question of what defines a cell's identity. Here we provide an overview of the major cardiac cell types, describe their roles in homeostasis, and outline recent findings on non-canonical functions that may be of relevance for cardiology. We highlight modes of biochemical and biophysical interactions between different cardiac cell types and discuss the potential implications of the heterocellular nature of the heart for basic research and therapeutic interventions.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"30"},"PeriodicalIF":7.5,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10372369","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":"Matrix metalloproteinase-2 proteolyzes mitofusin-2 and impairs mitochondrial function during myocardial ischemia-reperfusion injury.","authors":"Wesam Bassiouni, Robert Valencia, Zabed Mahmud, John M Seubert, Richard Schulz","doi":"10.1007/s00395-023-00999-y","DOIUrl":"10.1007/s00395-023-00999-y","url":null,"abstract":"<p><p>During myocardial ischemia and reperfusion (IR) injury matrix metalloproteinase-2 (MMP-2) is rapidly activated in response to oxidative stress. MMP-2 is a multifunctional protease that cleaves both extracellular and intracellular proteins. Oxidative stress also impairs mitochondrial function which is regulated by different proteins, including mitofusin-2 (Mfn-2), which is lost in IR injury. Oxidative stress and mitochondrial dysfunction trigger the NLRP3 inflammasome and the innate immune response which invokes the de novo expression of an N-terminal truncated isoform of MMP-2 (NTT-MMP-2) at or near mitochondria. We hypothesized that MMP-2 proteolyzes Mfn-2 during myocardial IR injury, impairing mitochondrial function and enhancing the inflammasome response. Isolated hearts from mice subjected to IR injury (30 min ischemia/40 min reperfusion) showed a significant reduction in left ventricular developed pressure (LVDP) compared to aerobically perfused hearts. IR injury increased MMP-2 activity as observed by gelatin zymography and increased degradation of troponin I, an intracellular MMP-2 target. MMP-2 preferring inhibitors, ARP-100 or ONO-4817, improved post-ischemic recovery of LVDP compared to vehicle perfused IR hearts. In muscle fibers isolated from IR hearts the rates of mitochondrial oxygen consumption and ATP production were impaired compared to those from aerobic hearts, whereas ARP-100 or ONO-4817 attenuated these reductions. IR hearts showed higher levels of NLRP3, cleaved caspase-1 and interleukin-1β in the cytosolic fraction, while the mitochondria-enriched fraction showed reduced levels of Mfn-2, compared to aerobic hearts. ARP-100 or ONO-4817 attenuated these changes. Co-immunoprecipitation showed that MMP-2 is associated with Mfn-2 in aerobic and IR hearts. ARP-100 or ONO-4817 also reduced infarct size and cell death in hearts subjected to 45 min ischemia/120 min reperfusion. Following myocardial IR injury, impaired contractile function and mitochondrial respiration and elevated inflammasome response could be attributed, at least in part, to MMP-2 activation, which targets and cleaves mitochondrial Mfn-2. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in IR injury in part by preserving Mfn-2 and suppressing inflammation.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"29"},"PeriodicalIF":9.5,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10372371","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":"Endothelial ILK induces cardioprotection by preventing coronary microvascular dysfunction and endothelial-to-mesenchymal transition.","authors":"P Reventun, S Sánchez-Esteban, A Cook-Calvete, M Delgado-Marín, C Roza, S Jorquera-Ortega, I Hernandez, L Tesoro, L Botana, J L Zamorano, C Zaragoza, M Saura","doi":"10.1007/s00395-023-00997-0","DOIUrl":"10.1007/s00395-023-00997-0","url":null,"abstract":"<p><p>Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/E' ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"28"},"PeriodicalIF":9.5,"publicationDate":"2023-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9824824","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":"A tale of pigs, beta-blockers and genetic variants.","authors":"Borja Ibáñez","doi":"10.1007/s00395-023-00998-z","DOIUrl":"10.1007/s00395-023-00998-z","url":null,"abstract":"","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"27"},"PeriodicalIF":9.5,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10174287","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":"Three-vessel coronary infusion of cardiosphere-derived cells for the treatment of heart failure with preserved ejection fraction in a pre-clinical pig model.","authors":"Romain Gallet, Jin-Bo Su, Daphné Corboz, Paul-Matthieu Chiaroni, Alain Bizé, Jianping Dai, Mathieu Panel, Pierre Boucher, Gaëtan Pallot, Juliette Brehat, Lucien Sambin, Guillaume Thery, Nadir Mouri, Aurélien de Pommereau, Pierre Denormandie, Stéphane Germain, Alain Lacampagne, Emmanuel Teiger, Eduardo Marbán, Bijan Ghaleh","doi":"10.1007/s00395-023-00995-2","DOIUrl":"10.1007/s00395-023-00995-2","url":null,"abstract":"<p><p>Heart failure with preserved ejection fraction (HFpEF) is a major public health concern. Its outcome is poor and, as of today, barely any treatments have been able to decrease its morbidity or mortality. Cardiosphere-derived cells (CDCs) are heart cell products with anti-fibrotic, anti-inflammatory and angiogenic properties. Here, we tested the efficacy of CDCs in improving left ventricular (LV) structure and function in pigs with HFpEF. Fourteen chronically instrumented pigs received continuous angiotensin II infusion for 5 weeks. LV function was investigated through hemodynamic measurements and echocardiography at baseline, after 3 weeks of angiotensin II infusion before three-vessel intra-coronary CDC (n = 6) or placebo (n = 8) administration and 2 weeks after treatment (i.e., at completion of the protocol). As expected, arterial pressure was significantly and similarly increased in both groups. This was accompanied by LV hypertrophy that was not affected by CDCs. LV systolic function remained similarly preserved during the whole protocol in both groups. In contrast, LV diastolic function was impaired (increases in Tau, LV end-diastolic pressure as well as E/A, E/E'septal and E/E'lateral ratios) but CDC treatment significantly improved all of these parameters. The beneficial effect of CDCs on LV diastolic function was not explained by reduced LV hypertrophy or increased arteriolar density; however, interstitial fibrosis was markedly reduced. Three-vessel intra-coronary administration of CDCs improves LV diastolic function and reduces LV fibrosis in this hypertensive model of HFpEF.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"118 1","pages":"26"},"PeriodicalIF":9.5,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10018328","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}