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Book ; Online ; Thesis: New approaches to the treatment of target organ damage in experimental models of hypertension

Sharkovska, Yuliya [Verfasser]

2012

Author's details	Yuliya Sharkovska
Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	English
Publisher	Medizinische Fakultät Charité - Universitätsmedizin Berlin
Publishing place	Berlin
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Reduction of cortical parvalbumin-expressing GABAergic interneurons in a rodent hyperoxia model of preterm birth brain injury with deficits in social behavior and cognition.

Scheuer, Till / dem Brinke, Elena Auf / Grosser, Sabine / Wolf, Susanne A / Mattei, Daniele / Sharkovska, Yuliya / Barthel, Paula C / Endesfelder, Stefanie / Friedrich, Vivien / Bührer, Christoph / Vida, Imre / Schmitz, Thomas

Development (Cambridge, England)

2021 Volume 148, Issue 20

Abstract: The inhibitory GABAergic system in the brain is involved in the etiology of various psychiatric problems, including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and others. These disorders are influenced not only by ... ...

Abstract	The inhibitory GABAergic system in the brain is involved in the etiology of various psychiatric problems, including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and others. These disorders are influenced not only by genetic but also by environmental factors, such as preterm birth, although the underlying mechanisms are not known. In a translational hyperoxia model, exposing mice pups at P5 to 80% oxygen for 48 h to mimic a steep rise of oxygen exposure caused by preterm birth from in utero into room air, we documented a persistent reduction of cortical mature parvalbumin-expressing interneurons until adulthood. Developmental delay of cortical myelin was observed, together with decreased expression of oligodendroglial glial cell-derived neurotrophic factor (GDNF), a factor involved in interneuronal development. Electrophysiological and morphological properties of remaining interneurons were unaffected. Behavioral deficits were observed for social interaction, learning and attention. These results demonstrate that neonatal oxidative stress can lead to decreased interneuron density and to psychiatric symptoms. The obtained cortical myelin deficit and decreased oligodendroglial GDNF expression indicate that an impaired oligodendroglial-interneuronal interplay contributes to interneuronal damage.
MeSH term(s)	Animals ; Brain Injuries/metabolism ; Cell Line ; Cognition/physiology ; Disease Models, Animal ; GABAergic Neurons/metabolism ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Hyperoxia/metabolism ; Interneurons/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Oligodendroglia/metabolism ; Parvalbumins/metabolism ; Premature Birth/metabolism ; Rodentia/metabolism ; Social Behavior
Chemical Substances	Glial Cell Line-Derived Neurotrophic Factor ; Parvalbumins
Language	English
Publishing date	2021-10-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.198390
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Article ; Online: Neonatal Hyperoxia Perturbs Neuronal Development in the Cerebellum.

Scheuer, Till / Sharkovska, Yuliya / Tarabykin, Victor / Marggraf, Katharina / Brockmöller, Vivien / Bührer, Christoph / Endesfelder, Stefanie / Schmitz, Thomas

Molecular neurobiology

2017 Volume 55, Issue 5, Page(s) 3901–3915

Abstract: Impaired postnatal brain development of preterm infants often results in neurological deficits. Besides pathologies of the forebrain, maldeveolopment of the cerebellum is increasingly recognized to contribute to psychomotor impairments of many former ... ...

Abstract	Impaired postnatal brain development of preterm infants often results in neurological deficits. Besides pathologies of the forebrain, maldeveolopment of the cerebellum is increasingly recognized to contribute to psychomotor impairments of many former preterm infants. However, causes are poorly defined. We used a hyperoxia model to define neonatal damage in cerebellar granule cell precursors (GCPs) and in Purkinje cells (PCs) known to be essential for interaction with GCPs during development. We exposed newborn rats to 24 h 80% O
MeSH term(s)	Animals ; Animals, Newborn ; Cell Count ; Cell Death/genetics ; Cell Proliferation/genetics ; Cerebellum/growth & development ; Cerebellum/pathology ; Dendrites/metabolism ; Gene Expression Regulation, Developmental ; Hedgehog Proteins/metabolism ; Hyperoxia/genetics ; Hyperoxia/pathology ; Neurogenesis ; Neurons/metabolism ; Neurons/pathology ; Purkinje Cells/metabolism ; Rats, Wistar
Chemical Substances	Hedgehog Proteins
Language	English
Publishing date	2017-05-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-017-0612-5
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Zs.A 2411: Show issues

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Article ; Online: The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats.

Hocher, Berthold / Sharkovska, Yuliya / Mark, Michael / Klein, Thomas / Pfab, Thiemo

International journal of cardiology

2013 Volume 167, Issue 1, Page(s) 87–93

Abstract: Background: Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem ... ...

Abstract	Background: Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia. Methods: Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min. Results: Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7%, p<0.05) and 8 weeks (-18.0%, p<0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals. Conclusions: Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4+ circulating progenitor cells.
MeSH term(s)	Animals ; Dipeptidyl Peptidase 4/physiology ; Dipeptidyl-Peptidase IV Inhibitors/chemistry ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Linagliptin ; Male ; Myocardial Infarction/drug therapy ; Myocardial Infarction/pathology ; Myocardial Reperfusion Injury/drug therapy ; Myocardial Reperfusion Injury/pathology ; Purines/chemistry ; Purines/therapeutic use ; Quinazolines/chemistry ; Quinazolines/therapeutic use ; Random Allocation ; Rats ; Rats, Wistar ; Xanthines/chemistry ; Xanthines/therapeutic use
Chemical Substances	8-(3-amino-1-piperidinyl)-7-(2-butyn-1-yl)-1-((4,6-dimethyl-2-pyrimidinyl)methyl)-3-methylxanthine ; Dipeptidyl-Peptidase IV Inhibitors ; Purines ; Quinazolines ; Xanthines ; Linagliptin (3X29ZEJ4R2) ; Dipeptidyl Peptidase 4 (EC 3.4.14.5)
Language	English
Publishing date	2013-07-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	779519-1
ISSN	1874-1754 ; 0167-5273
ISSN (online)	1874-1754
ISSN	0167-5273
DOI	10.1016/j.ijcard.2011.12.007
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Zs.A 1673: Show issues

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Article ; Online: Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy.

Sharkovska, Yuliya / Reichetzeder, Christoph / Alter, Markus / Tsuprykov, Oleg / Bachmann, Sebastian / Secher, Thomas / Klein, Thomas / Hocher, Berthold

Journal of hypertension

2014 Volume 32, Issue 11, Page(s) 2211–23; discussion 2223

Abstract: Background: Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear.: Method: This study examined the long-term renoprotective effects of DPP-4 inhibitor ... ...

Abstract	Background: Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear. Method: This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8). Results: Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well. Conclusion: Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.
MeSH term(s)	Albuminuria/etiology ; Albuminuria/prevention & control ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Animals ; Blood Pressure/physiology ; Diabetes Mellitus, Type 2/complications ; Diabetic Nephropathies/etiology ; Diabetic Nephropathies/prevention & control ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Disease Models, Animal ; Enalapril/therapeutic use ; Glucose/metabolism ; Hypoglycemic Agents/pharmacology ; Kidney/pathology ; Kidney Glomerulus/pathology ; Linagliptin/therapeutic use ; Male ; Mice ; Mice, Inbred Strains ; Renin-Angiotensin System/drug effects
Chemical Substances	Angiotensin-Converting Enzyme Inhibitors ; Dipeptidyl-Peptidase IV Inhibitors ; Hypoglycemic Agents ; Linagliptin (3X29ZEJ4R2) ; Enalapril (69PN84IO1A) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2014-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605532-1
ISSN	1473-5598 ; 0263-6352 ; 0952-1178
ISSN (online)	1473-5598
ISSN	0263-6352 ; 0952-1178
DOI	10.1097/HJH.0000000000000328
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Zs.A 1885: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 614: Show issues

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Article ; Online: Riociguat prevents fibrotic tissue remodelling and improves survival in salt-sensitive Dahl rats

Hucke Andreas / Lawrenz Bettina / Evgenov Oleg V / Sharkovska Yuliya / Kretschmer Axel / Geschka Sandra / Hocher Berthold / Stasch Johannes-Peter

BMC Pharmacology, Vol 11, Iss Suppl 1, p P

2011 Volume 28

Keywords	Therapeutics. Pharmacology ; RM1-950 ; Medicine ; R ; DOAJ:Therapeutics ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2011-08-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy.

Tsuprykov, Oleg / Ando, Ryotaro / Reichetzeder, Christoph / von Websky, Karoline / Antonenko, Viktoriia / Sharkovska, Yuliya / Chaykovska, Lyubov / Rahnenführer, Jan / Hasan, Ahmed A / Tammen, Harald / Alter, Markus / Klein, Thomas / Ueda, Seiji / Yamagishi, Sho-Ichi / Okuda, Seiya / Hocher, Berthold

Kidney international

2016 Volume 89, Issue 5, Page(s) 1049–1061

Abstract: Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing ... ...

Abstract	Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48% with linagliptin but a non-significant 24% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66% with linagliptin and 92% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different.
MeSH term(s)	Albuminuria/enzymology ; Albuminuria/prevention & control ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Benzimidazoles/pharmacology ; Benzoates/pharmacology ; Biomarkers/blood ; Blood Pressure/drug effects ; Chromatography, Liquid ; Dipeptidyl Peptidase 4/deficiency ; Dipeptidyl Peptidase 4/genetics ; Dipeptidyl Peptidase 4/metabolism ; Dipeptidyl-Peptidase IV Inhibitors/pharmacology ; Disease Models, Animal ; Disease Progression ; Fibrosis ; Kidney/drug effects ; Kidney/enzymology ; Kidney/pathology ; Linagliptin/pharmacology ; Male ; Mass Spectrometry ; Nephrectomy/methods ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Rats, Transgenic ; Renal Insufficiency, Chronic/drug therapy ; Renal Insufficiency, Chronic/enzymology ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/pathology ; Renin-Angiotensin System/drug effects ; Signal Transduction/drug effects ; Time Factors
Chemical Substances	Angiotensin II Type 1 Receptor Blockers ; Benzimidazoles ; Benzoates ; Biomarkers ; Dipeptidyl-Peptidase IV Inhibitors ; Linagliptin (3X29ZEJ4R2) ; DPP4 protein, rat (EC 3.4.14.5) ; Dipeptidyl Peptidase 4 (EC 3.4.14.5) ; telmisartan (U5SYW473RQ)
Language	English
Publishing date	2016-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2016.01.016
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Zs.A 797: Show issues

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Article ; Online: Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats.

Geschka, Sandra / Kretschmer, Axel / Sharkovska, Yuliya / Evgenov, Oleg V / Lawrenz, Bettina / Hucke, Andreas / Hocher, Berthold / Stasch, Johannes-Peter

PloS one

2011 Volume 6, Issue 7, Page(s) e21853

Abstract: Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including ... ...

Abstract	Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension. Methods and results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1. Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.
MeSH term(s)	Animals ; Biomarkers/blood ; Biomarkers/urine ; Blood Pressure/drug effects ; Body Weight/drug effects ; Echocardiography ; Fibrosis ; Gene Expression Regulation/drug effects ; Guanylate Cyclase/metabolism ; Heart Rate/drug effects ; Hemodynamics/drug effects ; Kidney/drug effects ; Kidney/pathology ; Kidney/physiopathology ; Kidney Function Tests ; Myocardium/pathology ; Organ Size/drug effects ; Organ Specificity/drug effects ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats ; Rats, Inbred Dahl ; Receptors, Cytoplasmic and Nuclear/metabolism ; Soluble Guanylyl Cyclase ; Survival Analysis ; Systole/drug effects
Chemical Substances	Biomarkers ; Pyrazoles ; Pyrimidines ; RNA, Messenger ; Receptors, Cytoplasmic and Nuclear ; Guanylate Cyclase (EC 4.6.1.2) ; Soluble Guanylyl Cyclase (EC 4.6.1.2) ; riociguat (RU3FE2Y4XI)
Language	English
Publishing date	2011-07-18
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0021853
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Article: Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage.

Sharkovska, Yuliya / Kalk, Philipp / von Websky, Karoline / Relle, Katharina / Pfab, Thiemo / Alter, Markus / Fischer, Yvan / Hocher, Berthold

Clinical laboratory

2011 Volume 57, Issue 7-8, Page(s) 507–515

Abstract: Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic ... ...

Abstract	Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure. Methods: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested. Results: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50% in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67% mortality in vehicle-treated rats, but only 20% after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case). Conclusions: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats.
MeSH term(s)	Acute Kidney Injury/drug therapy ; Acute Kidney Injury/etiology ; Albuminuria/etiology ; Albuminuria/prevention & control ; Animals ; Aspartic Acid Endopeptidases/antagonists & inhibitors ; Constriction ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Endothelin-Converting Enzymes ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Glomerulosclerosis, Focal Segmental/etiology ; Hypertension/chemically induced ; Hypertension/complications ; Kidney/blood supply ; Kidney Failure, Chronic/drug therapy ; Kidney Failure, Chronic/etiology ; Male ; Metalloendopeptidases/antagonists & inhibitors ; NG-Nitroarginine Methyl Ester/toxicity ; Nephrectomy ; Neprilysin/antagonists & inhibitors ; Rats ; Rats, Wistar ; Reperfusion Injury/complications ; Reperfusion Injury/drug therapy
Chemical Substances	Enzyme Inhibitors ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; Metalloendopeptidases (EC 3.4.24.-) ; Neprilysin (EC 3.4.24.11) ; Endothelin-Converting Enzymes (EC 3.4.24.71) ; NG-Nitroarginine Methyl Ester (V55S2QJN2X)
Language	English
Publishing date	2011
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1307629-2
ISSN	1433-6510 ; 0941-2131
ISSN	1433-6510 ; 0941-2131
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Article ; Online: 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.

Lauer, Dilyara / Slavic, Svetlana / Sommerfeld, Manuela / Thöne-Reineke, Christa / Sharkovska, Yuliya / Hallberg, Anders / Dahlöf, Bjorn / Kintscher, Ulrich / Unger, Thomas / Steckelings, Ulrike Muscha / Kaschina, Elena

Hypertension (Dallas, Tex. : 1979)

2014 Volume 63, Issue 3, Page(s) e60–7

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Blotting, Western ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Fibrosis/drug therapy ; Fibrosis/genetics ; Fibrosis/metabolism ; Gene Expression Regulation ; Heart Ventricles/drug effects ; Heart Ventricles/pathology ; Heart Ventricles/physiopathology ; Male ; Matrix Metalloproteinase 1/genetics ; Matrix Metalloproteinase 1/metabolism ; Matrix Metalloproteinase 9/genetics ; Matrix Metalloproteinase 9/metabolism ; RNA/genetics ; Rats ; Rats, Wistar ; Real-Time Polymerase Chain Reaction ; Receptor, Angiotensin, Type 2/agonists ; Receptor, Angiotensin, Type 2/metabolism ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta1/metabolism ; Ventricular Dysfunction, Left/drug therapy ; Ventricular Dysfunction, Left/genetics ; Ventricular Dysfunction, Left/metabolism ; Ventricular Function, Left ; Ventricular Remodeling
Chemical Substances	Receptor, Angiotensin, Type 2 ; Transforming Growth Factor beta1 ; RNA (63231-63-0) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Matrix Metalloproteinase 1 (EC 3.4.24.7)
Language	English
Publishing date	2014-03
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.113.02522
Database	MEDical Literature Analysis and Retrieval System OnLINE

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