Elena Kaschina

Charité - Universitätsmedizin Berlin

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Thomas Unger

Maastricht University

Manuela Sommerfeld

Humboldt-Universität zu Berlin

U. Muscha Steckelings

University of Southern Denmark

Ulrich Kintscher

Charité - Universitätsmedizin Berlin

Christa Thöne‐Reineke

Freie Universität Berlin

Svetlana Slavić

University of Veterinary Medicine Vienna

Dilyara Lauer

Charité - Universitätsmedizin Berlin

Aleksandra Grzesiak

Charité - Universitätsmedizin Berlin

Vijayalakshmi Sridharan

University of Arkansas for Medical Sciences

Marjan Boerma

University of Arkansas for Medical Sciences

Cooperative Institutions

Charité - Universitätsmedizin Berlin

134

Humboldt-Universität zu Berlin

Freie Universität Berlin

German Centre for Cardiovascular Research

Deutsches Herzzentrum der Charité

Berlin Institute of Health at Charité - Universitätsmedizin Berlin

Universidade Federal de Minas Gerais

Monash University

Heidelberg University

Maastricht University

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Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

The Journal of Immunology (2010)

Caterina Curato Svetlana Slavić Jun Dong Anna Skorska Wassim Altarche‐Xifró

Abstract Emerging evidence suggests a cardioprotective role of the angiotensin AT2R, albeit the underlying cellular mechanisms are not well understood. We aimed in this article to elucidate a potential role of cardiac angiotensin AT2R in regulating cellular immune response to ischemic heart injury. Seven days after myocardial infarction in rats, double-immunofluorescence staining showed that AT2R was detected in a fraction of CD8+ T cells infiltrating in the peri-infarct myocardium. We developed a method that allowed the isolation of myocardial infiltrating CD8+AT2R+ T cells using modified MACS, and further characterization and purification with flow cytometry. Although the CD8+AT2R− T cells exhibited potent cytotoxicity to both adult and fetal cardiomyocytes (CMs), the CD8+AT2R+ T cells were noncytotoxic to these CMs. The CD8+AT2R+ T cells were characterized by upregulated IL-10 and downregulated IL-2 and INF-γ expression when compared with CD8+AT2R− T cells. We further showed that IL-10 gene expression was enhanced in CD8+ T cells on in vitro AT2R stimulation. Importantly, in vivo AT2R activation engendered an increment of CD8+AT2R+ T cells and IL-10 production in the ischemic myocardium. In addition, intramyocardial transplantation of CD8+AT2R+ T cells (versus CD8+AT2R−) led to reduced ischemic heart injury. Moreover, the CD8+AT2R+ T cell population was also demonstrated in human peripheral blood. Thus, we have defined the cardioprotective CD8+AT2R+ T cell population, which increases during ischemic heart injury and contributes to maintaining CM viability and providing IL-10, hence revealing an AT2R-mediated cellular mechanism in modulating adaptive immune response in the heart.

10.4049/jimmunol.0903681

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Citations (94)

AT2 receptors in cardiovascular and renal diseases

Pharmacological Research (2017)

Elena Kaschina Pawel Namsolleck Thomas Unger

The renin-angiotensin system (RAS) plays an important role in the initiation and progression of cardiovascular and renal diseases. These actions mediated by AT1 receptor (AT1R) are well established and led to development of selective AT1R blockers (ARBs). In contrast, there is scientific evidence that AT2 receptor (AT2R) mediates effects different from and often opposing those of the AT1R. Meagrely expressed in healthy tissue the AT2R is upregulated in injuries providing an endogenous protection to inflammatory, oxidative and apoptotic processes. Interestingly the beneficial effects mediated by AT2R can be further enhanced by pharmacological intervention using the recently developed AT2R agonists. This review article summarizes our current knowledge about regulation, signalling and effects mediated by AT2R in health and disease, with emphasis on cardiac and renal systems. At the end a novel concept of natural protective systems will be introduced and discussed as an attractive target in drug development.

10.1016/j.phrs.2017.07.008

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Citations (108)

Angiotensin Type 2 Receptor Stimulation Ameliorates Left Ventricular Fibrosis and Dysfunction via Regulation of Tissue Inhibitor of Matrix Metalloproteinase 1/Matrix Metalloproteinase 9 Axis and Transforming Growth Factor β1 in the Rat Heart

Hypertension (2013)

Dilyara Lauer Svetlana Slavić Manuela Sommerfeld Christa Thöne‐Reineke Yuliya Sharkovska

Left ventricular (LV) remodeling is the main reason for the development of progressive cardiac dysfunction after myocardial infarction (MI). This study investigated whether stimulation of the angiotensin type 2 receptor is able to ameliorate post-MI cardiac remodeling and what the underlying mechanisms may be. MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with the angiotensin type 2 receptor agonist compound 21 ( 0.03 mg/kg) was started 6 hours post-MI and continued for 6 weeks. Hemodynamic parameters were measured by echocardiography and intracardiac catheter. Effects on proteolysis were studied in heart tissue and primary cardiac fibroblasts. Compound 21 significantly improved systolic and diastolic functions, resulting in improved ejection fraction (71.2±4.7% versus 53.4±7.0%; P <0.001), fractional shortening ( P <0.05), LV internal dimension in systole ( P <0.05), LV end-diastolic pressure (16.9±1.2 versus 22.1±1.4 mm Hg; P <0.05), ratio of early (E) to late (A) ventricular filling velocities, and maximum and minimum rate of LV pressure rise ( P <0.05). Compound 21 improved arterial stiffness parameters and reduced collagen content in peri-infarct myocardium. Tissue inhibitor of matrix metalloproteinase 1 was strongly upregulated, whereas matrix metalloproteinases 2 and 9 and transforming growth factor β1 were diminished in LV of treated animals. In cardiac fibroblasts, compound 21 initially induced tissue inhibitor of matrix metalloproteinase 1 expression followed by attenuated matrix metalloproteinase 9 and transforming growth factor β1 secretion. In conclusion, angiotensin type 2 receptor stimulation improves cardiac function and prevents cardiac remodeling in the late stage after MI, suggesting that angiotensin type 2 receptor agonists may be considered a future pharmacological approach for the improvement of post-MI cardiac dysfunction.

Cardiac Fibrosis

Ventricular remodeling

10.1161/hypertensionaha.113.02522

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Citations (76)

Efficacy of empagliflozine in experimental chronic heart failure in normoglycemia

Cardiology News Opinions Training (2021)

Alexander N. Kulikov М. В. Краснова D. Yu. Ivkin А. А. Карпов Elena Kaschina

10.33029/2309-1908-2021-9-1-9-16

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Citations (1)

Comparative efficacy of empagliflozin and drugs of baseline therapy in post-infarct heart failure in normoglycemic rats

Naunyn-Schmiedeberg s Archives of Pharmacology (2020)

М. В. Краснова А. Н. Куликов Sergey V. Okovityi D. Yu. Ivkin А. А. Карпов

Empagliflozin

Fosinopril

Bisoprolol

Irbesartan

Carvedilol

10.1007/s00210-020-01873-7

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Citations (13)

Pathophysiologic Link between Atherosclerosis and Nephrosclerosis

Springer eBooks (2010)

Elena Kaschina Thomas Unger

Glomerulosclerosis

10.1007/978-88-470-1463-3_18

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Citations (1)

UPREGULATED ANGIOTENSIN AT1 RECEPTORS ASSOCIATE WITH APOPTOSIS INDUCTION IN CARDIOMYOCYTES AFTER MYOCARDIAL INFARCTION IN RATS

Journal of Hypertension (2004)

J. Li Kamal Elkhrbash Elena Kaschina M. Timm Thomas Linger

Center for Cardiovascular Research (CCR) Iinstitute of Pharmacology and Toxicology, Charite Mitte, Berlin, Germany

10.1097/00004872-200406002-00127

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Angiotensin II type 2 receptors: signalling and pathophysiological role

Current Opinion in Nephrology & Hypertension (2001)

Annegret Blume Elena Kaschina Thomas Unger

The signalling mechanisms and biological significance of the angiotensin II type 2 receptor have long been unknown. In recent years, studies, first in cell culture models but now increasingly also in vivo, have shed some light on the molecular events occurring after a stimulation of the receptor with its ligand as well as on its physiological effects and its significance for pathophysiological processes. There is increasing evidence that the angiotensin II type 2 receptor is involved in different pathophysiological processes, such as myocardial infarction, heart and kidney failure, and stroke.

Pathophysiology

Cell type

10.1097/00041552-200103000-00013

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Citations (25)

Supplementary Material for: Long-Term Angiotensin II Receptor Blockade Limits Hypertension, Aortic Dysfunction, and Structural Remodeling in a Rat Model of Chronic Kidney Disease

Figshare (2016)

Omar Z. Ameer Mark Butlin Elena Kaschina Manuela Sommerfeld Alberto Avolio

Background/Aims: Chronic kidney disease (CKD) is associated with large artery remodeling, endothelial dysfunction and calcification, with angiotensin II (Ang II) a known driver of these pathologies. We investigated long-term Ang II type 1 receptor inhibition with valsartan on aortic function and structure in the Lewis polycystic kidney (LPK) rat model of CKD. Methods: Mixed sex LPK and Lewis control (total n = 28) treated (valsartan 60 mg/kg/day p.o. from 4 to 18 weeks) and vehicle groups were studied. Functional responses to noradrenaline (NA), potassium chloride and endothelium-dependent and independent relaxations were investigated in vitro using acetylcholine hydrochloride (ACh) and sodium nitroprusside (SNP), respectively. Effects of the nitric oxide synthase (NOS) substrate L-arginine, NOS inhibitor L-NAME and cyclooxygenase inhibitor indomethacin on ACh responses were examined. Results: In the LPK, valsartan reduced systolic blood pressure and urinary protein, ameliorated exaggerated sensitivity to NA, and normalized endothelium-dependent (ACh-R_max; 91 ± 7 vs. 59 ± 6%, p = 0.0001) and independent dysfunction (SNP-R_max; 99 ± 1 vs. 82 ± 7%, p = 0.040), as well as improving NO-dependent relaxation (R_max; -51 ± 6 vs. -26 ± 9%, p = 0.008). Valsartan also reduced aortic wall hypertrophy, elastin disruption/fragmentation, calcification, media cystic degeneration, and levels of matrix metalloproteinase 9. Conclusions: This study highlights the role of Ang II in driving vascular manifestations of CKD and indicates that early treatment can significantly limit pathological changes.

10.6084/m9.figshare.4249907

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Citations (0)

Telmisartan prevents aneurysm progression in the rat by inhibiting proteolysis, apoptosis and inflammation

Journal of Hypertension (2008)

Elena Kaschina Felix Schrader Manuela Sommerfeld Ulrich Rudolf Kemnitz Aleksandra Grzesiak

Objectives We investigated the effects of treatment with the angiotensin II type 1 receptor antagonist, telmisartan, on abdominal aortic aneurysm formation in normotensive rats. Methods Abdominal aortic aneurysm was induced by perfusion of an isolated aortic segment with elastase. Treatment with telmisattan (0.5 mg/kg per day) or hydralazine (15 mg/kg per day) was started after surgery and continued for 14 days. Sham-operated animals and vehicle-treated animals after aneurysm induction served as controls. Aortic diameter was measured using ultrasound before aneurysm induction and on days 7 and 14 after aneurysm induction. Results On day 14, aortic diameter was increased two-fold in the vehicle-treated group compared to sham-operated animals (2.02 ± 0.12 vs. 0.87 ± 0.02 mm, P < 0.005, n = 8). Telmisartan treatment significantly reduced aneurysmal size (1.65 ± 0.06 vs. 2.02 ± 0.12 mm in vehicle, P < 0.05, n = 8), whereas treatment with hydralazine had no effect. Matrix metallopeptidase 3, cathepsin D, nuclear factor kappa B, tumour necrosis factor alpha, transforming growth factor-1 beta, as well as caspase 3, p53 and Fas ligand proteins, were significantly downregulated in aortic tissue under telmisartan compared to vehicle treatment. Serum monocyte chemoattractant protein 1 levels were also significantly decreased. Telmisartan and hydralazine reduced blood pressure to a similar extent within the observation period. Conclusion The angiotensin II type 1 receptor antagonist, telmisartan, prevents abdominal aortic aneurysm progression independently of blood pressure reduction by inhibiting proteolysis, apoptosis and inflammation in aortic tissue.

Proteolysis

Telmisartan

10.1097/hjh.0b013e328313e547

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Citations (59)