Basic Research in Cardiology最新文献

{"title":"Investigating the cause of cardiovascular dysfunction in chronic kidney disease: capillary rarefaction and inflammation may contribute to detrimental cardiovascular outcomes","authors":"Siavash Beikoghli Kalkhoran, Maryna Basalay, Zhenhe He, Pelin Golforoush, Tayeba Roper, Ben Caplin, Alan D. Salama, Sean M. Davidson, Derek M. Yellon","doi":"10.1007/s00395-024-01086-6","DOIUrl":"https://doi.org/10.1007/s00395-024-01086-6","url":null,"abstract":"<p>Myocardial ischemia–reperfusion (IR) injury is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD). The most frequently used and representative experimental model is the rat dietary adenine-induced CKD, which leads to CKD-associated CVD. However, the continued intake of adenine is a potential confounding factor. This study investigated cardiovascular dysfunction following brief adenine exposure, CKD development and return to a normal diet. Male Wistar rats received a 0.3% adenine diet for 10 weeks and normal chow for an additional 8 weeks. Kidney function was assessed by urinalysis and histology. Heart function was assessed by echocardiography. Sensitivity to myocardial IR injury was assessed using the isolated perfused rat heart (Langendorff) model. The inflammation profile of rats with CKD was assessed via cytokine ELISA, tissue histology and RNA sequencing. Induction of CKD was confirmed by a significant increase in plasma creatinine and albuminuria. Histology revealed extensive glomerular and tubular damage. Diastolic dysfunction, measured by the reduction of the E/A ratio, was apparent in rats with CKD even following a normal diet. Hearts from rats with CKD had significantly larger infarcts after IR injury. The CKD rats also had statistically higher levels of markers of inflammation including myeloperoxidase, KIM-1 and interleukin-33. RNA sequencing revealed several changes including an increase in inflammatory signaling pathways. In addition, we noted that CKD induced significant cardiac capillary rarefaction. We have established a modified model of adenine-induced CKD, which leads to cardiovascular dysfunction in the absence of adenine. Our observations of capillary rarefaction and inflammation suggest that these may contribute to detrimental cardiovascular outcomes.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"15 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541628","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 IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT): multicenter pig study on the effect of ischemic preconditioning","authors":"Petra Kleinbongard, Carlos Galán Arriola, Lina Badimon, Veronica Crisostomo, Zoltán Giricz, Mariann Gyöngyösi, Gerd Heusch, Borja Ibanez, Attila Kiss, Dominique P. V. de Kleijn, Bruno K. Podesser, Rafael Ramírez Carracedo, Antonio Rodríguez-Sinovas, Marisol Ruiz-Meana, Francisco M. Sanchez Margallo, Gemma Vilahur, José Luis Zamorano, Carlos Zaragoza, Peter Ferdinandy, Derek J. Hausenloy","doi":"10.1007/s00395-024-01083-9","DOIUrl":"https://doi.org/10.1007/s00395-024-01083-9","url":null,"abstract":"<p>Numerous cardioprotective interventions have been reported to reduce myocardial infarct size (IS) in pre-clinical studies. However, their translation for the benefit of patients with acute myocardial infarction (AMI) has been largely disappointing. One reason for the lack of translation is the lack of rigor and reproducibility in pre-clinical studies. To address this, we have established the European IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) pig AMI network with centralized randomization and blinded core laboratory IS analysis and validated the network with ischemic preconditioning (IPC) as a positive control. Ten sites in the COST Innovators Grant (IG16225) network participated in the IMPACT network. Three sites were excluded from the final analysis through quality control of infarct images and use of pre-defined exclusion criteria. Using a centrally generated randomization list, pigs were allocated to myocardial ischemia/reperfusion (I/R, <i>N</i> = 5/site) or IPC + I/R (<i>N</i> = 5/site). The primary endpoint was IS [% area-at-risk (AAR)], as quantified by triphenyl-tetrazolium-chloride (TTC) staining in a centralized, blinded core laboratory (5 sites), or IS [% left-ventricular mass (LV)], as quantified by a centralized, blinded cardiac magnetic resonance (CMR) core laboratory (2 sites). In pooled analyses, IPC significantly reduced IS when compared to I/R (57 ± 14 versus 32 ± 19 [%AAR] <i>N</i> = 25 pigs/group; <i>p</i> &lt; 0.001; 25 ± 13 versus 14 ± 8 [%LV]; <i>N</i> = 10 pigs/group; <i>p</i> = 0.021). In site-specific analyses, in 4 of the 5 sites, IS was significantly reduced by IPC when compared to I/R when quantified by TTC and in 1 of 2 sites when quantified by CMR. A pig AMI multicenter European network with centralized randomization and core blinded IS analysis was established and validated with the aim to improve the reproducibility of cardioprotective interventions in pre-clinical studies and the translation of cardioprotection for patient benefit.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"24 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448934","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":"CAESAR lives on with IMPACT: bringing rigor and relevance to cardioprotection research.","authors":"Roberto Bolli,Xian-Liang Tang","doi":"10.1007/s00395-024-01082-w","DOIUrl":"https://doi.org/10.1007/s00395-024-01082-w","url":null,"abstract":"","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"14 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449314","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":"Oxidative stress initiates hemodynamic change in CKD-induced heart disease.","authors":"Payel Sen,Jules Hamers,Theresa Sittig,Bachuki Shashikadze,Laura d'Ambrosio,Jan B Stöckl,Susanne Bierschenk,Hengliang Zhang,Chiara d'Alessio,Lotte M Zandbergen,Valerie Pauly,Sebastian Clauss,Eckhard Wolf,Andreas Dendorfer,Thomas Fröhlich,Daphne Merkus","doi":"10.1007/s00395-024-01085-7","DOIUrl":"https://doi.org/10.1007/s00395-024-01085-7","url":null,"abstract":"Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial structure and oxidative stress. However, CKD was combined with metabolic derangement, thereby obscuring the contribution of CKD alone. Therefore, we studied the impact of CKD on the heart and combined proteome studies with measurement of cardiac function and perfusion to identify processes involved in cardiac remodeling in CKD. CKD was induced in swine at 10-12 weeks of age while sham-operated swine served as controls. 5-6 months later, left ventricular (LV) function and coronary flow reserve were measured. LC-MS-MS-based proteomic analysis of LV tissue was performed. LV myocardium and kidneys were histologically examined for interstitial fibrosis and oxidative stress. Renal embolization resulted in mild chronic kidney injury (increased fibrosis and urinary NGAL). PV loops showed LV dilation and increased wall stress, while preload recruitable stroke work was impaired in CKD. Quantitative proteomic analysis of LV myocardium and STRING pre-ranked functional analysis showed enrichments in pathways related to contractile function, reactive oxygen species, and extracellular matrix (ECM) remodeling, which were confirmed histologically and associated with impaired total anti-oxidant capacity. H2O2 exposure of myocardial slices from CKD, but not normal swine, impaired contractile function. Furthermore, in CKD, mitochondrial proteins were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow. Thus, mild CKD induces alterations in mitochondrial proteins along with contractile proteins, oxidative stress and ECM remodeling, that were associated with changes in cardiac function and perfusion.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"59 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439657","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":"Macrophages enhance sodium channel expression in cardiomyocytes","authors":"N. V. Bogert, M. Therre, S. Din, J. Furkel, X. Zhou, I. El-Battrawy, J. Heineke, P. A. Schweizer, I. Akin, H. A. Katus, N. Frey, F. Leuschner, M. H. Konstandin","doi":"10.1007/s00395-024-01084-8","DOIUrl":"https://doi.org/10.1007/s00395-024-01084-8","url":null,"abstract":"<p>Cardiac macrophages facilitate electrical conduction through the atrioventricular-node (AV) in mice. A possible role for cardiomyocyte-macrophage coupling on the effect of antiarrhythmic therapy has not been investigated yet. Holter monitoring was conducted in LysM^CrexCsf1r^LsL−DTR mice (MM^DTR) under baseline conditions and after an elctrophysiological stress test by flecainide. In vivo effects were recapitulated in vitro by patch-clamp experiments. The underlying mechanism was characterized by expression and localization analysis of connexin43 (Cx43) and voltage-gated-sodium-channel-5 (Na_v1.5). ECG monitoring in MM^DTR mice did not show any significant conduction abnormalities but a significantly attenuated flecainide-induced extension of RR- and PP-intervals. Patch-clamp analysis revealed that the application of flecainide to neonatal rat ventricular cardiomyocytes (CMs) changed their resting-membrane-potential (RMP) to more negative potentials and decreased action-potential-duration (APD50). Coupling of macrophages to CMs significantly enhances the effects of flecainide, with a further reduction of the RMP and APD50, mediated by an upregulation of Cx43 and Na_v1.5 surface expression. Macrophage depletion in mice does not correlate with cardiac electric conduction delay. Cardiac macrophages amplify the effects of flecainide on electrophysiological properties of cardiomyocytes in vivo and in vitro<i>.</i> Mechanistically, formation of macrophage-cardiomyocyte cell–cell-contacts via Cx43 facilitates the recruitment of Na_v1.5 to the cell membrane increasing flecainide effects.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"8 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385579","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":"Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca²⁺ channel.","authors":"Dragos Andrei Duse, Nathalie Hannelore Schröder, Tanu Srivastava, Marcel Benkhoff, Jens Vogt, Melissa Kim Nowak, Florian Funk, Nina Semleit, Philipp Wollnitzke, Ralf Erkens, Sebastian Kötter, Sven Günther Meuth, Petra Keul, Webster Santos, Amin Polzin, Malte Kelm, Martina Krüger, Joachim Schmitt, Bodo Levkau","doi":"10.1007/s00395-024-01073-x","DOIUrl":"10.1007/s00395-024-01073-x","url":null,"abstract":"<p><p>The erythrocyte S1P transporter Mfsd2b is also expressed in the heart. We hypothesized that S1P transport by Mfsd2b is involved in cardiac function. Hypertension-induced cardiac remodeling was induced by 4-weeks Angiotensin II (AngII) administration and assessed by echocardiography. Ca²⁺ transients and sarcomere shortening were examined in adult cardiomyocytes (ACM) from Mfsd2b^+/+ and Mfsd2b^-/- mice. Tension and force development were measured in skinned cardiac fibers. Myocardial gene expression was determined by real-time PCR, Protein Phosphatase 2A (PP2A) by enzymatic assay, and S1P by LC/MS, respectively. Msfd2b was expressed in the murine and human heart, and its deficiency led to higher cardiac S1P. Mfsd2b^-/- mice had regular basal cardiac function but were protected against AngII-induced deterioration of left-ventricular function as evidenced by ~ 30% better stroke volume and cardiac index, and preserved ejection fraction despite similar increases in blood pressure. Mfsd2b^-/- ACM exhibited attenuated Ca²⁺ mobilization in response to isoprenaline whereas contractility was unchanged. Mfsd2b^-/- ACM showed no changes in proteins responsible for Ca²⁺ homeostasis, and skinned cardiac fibers exhibited reduced passive tension generation with preserved contractility. Verapamil abolished the differences in Ca²⁺ mobilization between Mfsd2b^+/+ and Mfsd2b^-/- ACM suggesting that S1P inhibits L-type-Ca²⁺ channels (LTCC). In agreement, intracellular S1P activated the inhibitory LTCC phosphatase PP2A in ACM and PP2A activity was increased in Mfsd2b^-/- hearts. We suggest that myocardial S1P protects from hypertension-induced left-ventricular remodeling by inhibiting LTCC through PP2A activation. Pharmacologic inhibition of Mfsd2b may thus offer a novel approach to heart failure.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"853-868"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896648","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":"Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2.","authors":"Sha Chen, Qian Wang, Diane Bakker, Xin Hu, Liping Zhang, Ingeborg van der Made, Anna M Tebbens, Csenger Kovácsházi, Zoltán Giricz, Gábor B Brenner, Peter Ferdinandy, Gert Schaart, Anne Gemmink, Matthijs K C Hesselink, Mathilde R Rivaud, Michael P Pieper, Markus W Hollmann, Nina C Weber, Jean-Luc Balligand, Esther E Creemers, Ruben Coronel, Coert J Zuurbier","doi":"10.1007/s00395-024-01067-9","DOIUrl":"10.1007/s00395-024-01067-9","url":null,"abstract":"<p><p>Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"751-772"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750941","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":"β3-Adrenergic receptor overexpression in cardiomyocytes preconditions mitochondria to withstand ischemia-reperfusion injury.","authors":"Miguel Fernández-Tocino, Andrés Pun-Garcia, Mónica Gómez, Agustín Clemente-Moragón, Eduardo Oliver, Rocío Villena-Gutierrez, Sofía Trigo-Anca, Anabel Díaz-Guerra, David Sanz-Rosa, Belén Prados, Lara Del Campo, Vicente Andrés, Valentín Fuster, José Luis de la Pompa, Laura Cádiz, Borja Ibañez","doi":"10.1007/s00395-024-01072-y","DOIUrl":"10.1007/s00395-024-01072-y","url":null,"abstract":"<p><p>β3-Adrenergic receptor (β3AR) agonists have been shown to protect against ischemia-reperfusion injury (IRI). Since β3ARs are present both in cardiomyocytes and in endothelial cells, the cellular compartment responsible for this protection has remained unknown. Using transgenic mice constitutively expressing the human β3AR (hβ3AR) in cardiomyocytes or in the endothelium on a genetic background of null endogenous β3AR expression, we show that only cardiomyocyte expression protects against IRI (45 min ischemia followed by reperfusion over 24 h). Infarct size was also limited after ischemia-reperfusion in mice with cardiomyocyte hβ3AR overexpression on top of endogenous β3AR expression. hβ3AR overexpression in these mice reduced IRI-induced cardiac fibrosis and improved long-term left ventricular systolic function. Cardiomyocyte-specific β3AR overexpression resulted in a baseline remodeling of the mitochondrial network, characterized by upregulated mitochondrial biogenesis and a downregulation of mitochondrial quality control (mitophagy), resulting in elevated numbers of small mitochondria with a depressed capacity for the generation of reactive oxygen species but improved capacity for ATP generation. These processes precondition cardiomyocyte mitochondria to be more resistant to IRI. Upon reperfusion, hearts with hβ3AR overexpression display a restoration in the mitochondrial quality control and a rapid activation of antioxidant responses. Strong protection against IRI was also observed in mice infected with an adeno-associated virus (AAV) encoding hβ3AR under a cardiomyocyte-specific promoter. These results confirm the translational potential of increased cardiomyocyte β3AR expression, achieved either naturally through exercise or artificially through gene therapy approaches, to precondition the cardiomyocyte mitochondrial network to withstand future insults.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"773-794"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970536","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":"Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.","authors":"Sourav Kundu, Shobhit Gairola, Smriti Verma, Madhav Nilakanth Mugale, Bidya Dhar Sahu","doi":"10.1007/s00395-024-01056-y","DOIUrl":"10.1007/s00395-024-01056-y","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"831-852"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070075","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 Gα_i2 in neutrophils protects from myocardial ischemia reperfusion injury.","authors":"David Köhler, Veronika Leiss, Lukas Beichert, Simon Killinger, Daniela Grothe, Ragini Kushwaha, Agnes Schröter, Anna Roslan, Claudia Eggstein, Jule Focken, Tiago Granja, Vasudharani Devanathan, Birgit Schittek, Robert Lukowski, Bettina Weigelin, Peter Rosenberger, Bernd Nürnberg, Sandra Beer-Hammer","doi":"10.1007/s00395-024-01057-x","DOIUrl":"10.1007/s00395-024-01057-x","url":null,"abstract":"<p><p>Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα_i proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gα_i2 proteins in resident cardiac vs circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gα_i2 in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR) Gnai2^-/- → wt vs 44.0% wt → wt; p < 0.001) whereas the absence of Gα_i2 in non-hematopoietic cells increased the infarct damage (66.5% wt → Gnai2^-/- vs 44.0% wt → wt; p < 0.001). Previously we have reported the impact of platelet Gα_i2 for mIRI. Here, we show that infarct size was substantially reduced when Gα_i2 signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9% Gnai2^fl/fl LysM-Cre^+/tg vs 42.0% Gnai2^fl/fl; p < 0.01) or selectively blocked with specific antibodies directed against Gα_i2 (AAR: 19.0% (anti-Gα_i2) vs 49.0% (IgG); p < 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (Gnai2^fl/fl; LysM-Cre^+/tg) vs 31 (Gnai2^fl/fl); p < 0.001) and in anti-Gα_i2 antibody-treated (PNCs: 9 (anti-Gα_i2) vs 33 (IgG); p < 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gα_i2 antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gα_i2 antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG) vs 13,225 (anti-Gα_i2) neutrophils; p < 0.001), collectively suggesting that a therapeutic concept of functional Gα_i2 inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"717-732"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141173771","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}