@article{MTMT:3331936, title = {Feasibility Evaluation of Myocardial Cannabinoid Type 1 Receptor Imaging in Obesity: A Translational Approach}, url = {https://m2.mtmt.hu/api/publication/3331936}, author = {Valenta, I and Varga, Zoltán and Valentine, H and Cinar, R and Horti, A and Mathews, WB and Dannals, RF and Steele, K and Kunos, G and Wahl, RL and Pomper, MG and Wong, DF and Pacher, Pál and Schindler, TH}, doi = {10.1016/j.jcmg.2017.11.019}, journal-iso = {JACC-CARDIOVASC IMAG}, journal = {JACC-CARDIOVASCULAR IMAGING}, volume = {11}, unique-id = {3331936}, issn = {1936-878X}, abstract = {OBJECTIVES: The aim of this study was to evaluate the feasibility of targeted imaging of myocardial cannabinoid type 1 receptor (CB1-R) and its potential up-regulation in obese mice with translation to humans using [(11)C]-OMAR and positron emission tomography (PET)/computed tomography (CT). BACKGROUND: Activation of myocardial CB1-R by endocannabinoids has been implicated in cardiac dysfunction in diabetic mice. Obesity may lead to an up-regulation of myocardial CB1-R, potentially providing a mechanistic link between obesity and the initiation and/or progression of cardiomyopathy. METHODS: Binding specificity of [(11)C]-OMAR to CB1-R was investigated by blocking studies with rimonabant in mice. The heart was harvested from each mouse, and its radioactivity was determined by gamma-counter. Furthermore, [(11)C]-OMAR dynamic micro-PET/CT was carried out in obese and normal-weight mice. Ex vivo validation was performed by droplet digital polymerase chain reaction (absolute quantification) and RNAscope Technology (an in situ ribonucleic acid analysis platform). Subsequently, myocardial CB1-R expression was probed noninvasively with intravenous injection of CB1-R ligand [(11)C]-OMAR and PET/CT in humans with advanced obesity and normal-weight human control subjects, respectively. RESULTS: Rimonabant significantly blocked OMAR uptake in the heart muscle compared with vehicle, signifying specific binding of OMAR to the CB1-R in the myocardium. The myocardial OMAR retention quantified by micro-PET/CT in mice was significantly higher in obese compared with normal-weight mice. Absolute quantification of CB1-R gene expression with droplet digital polymerase chain reaction and in situ hybridization confirmed CB1-R up-regulation in all major myocardial cell types (e.g., cardiomyocytes, endothelium, vascular smooth muscle cells, and fibroblasts) of obese mice. Obese mice also had elevated myocardial levels of endocannabinoids anandamide and 2-arachidonoylglycerol compared with lean mice. Translation to humans revealed higher myocardial OMAR retention in advanced obesity compared with normal-weight subjects. CONCLUSIONS: Noninvasive imaging of cardiac CB1-R expression in obesity is feasible applying [(11)C]-OMAR and PET/CT. These results may provide a rationale for further clinical testing of CB1-R-targeted molecular imaging in cardiometabolic diseases.}, year = {2018}, eissn = {1876-7591}, pages = {320-332}, orcid-numbers = {Varga, Zoltán/0000-0002-2758-0784; Pacher, Pál/0000-0001-7036-8108} } @article{MTMT:3358897, title = {Disruption of renal arginine metabolism promotes kidney injury in hepatorenal syndrome in mice}, url = {https://m2.mtmt.hu/api/publication/3358897}, author = {Varga, Zoltán and Erdélyi, Katalin and Paloczi, J and Cinar, R and Zsengeller, ZK and Jourdan, T and Mátyás, Csaba and Németh, Balázs Tamás and Guillot, A and Xiang, X and Mehal, A and Haskó, György and Stillman, IE and Rosen, S and Gao, B and Kunos, G and Pacher, Pál}, doi = {10.1002/hep.29915}, journal-iso = {HEPATOLOGY}, journal = {HEPATOLOGY}, volume = {68}, unique-id = {3358897}, issn = {0270-9139}, abstract = {Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end-stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile-duct ligation (BDL)-induced hepatic and renal injury in mice in vivo by using biochemical assays, real-time PCR, Western blot, mass spectrometry, histology and electron microscopy. BDL resulted in time-dependent hepatic injury and hyperammonemia which were paralleled by tubular dilation and tubulointerstitial nephritis with marked upregulation of lipocalin-2, KIM-1 and osteopontin. Renal injury was associated with dramatically impaired microvascular flow and decreased endothelial nitric oxide synthase (eNOS) activity. Gene expression analyses signified proximal tubular epithelial injury, tissue hypoxia, inflammation, and activation of the fibrotic gene program. Marked changes in renal arginine metabolism (upregulation of arginase-2 and downregulation of argininosuccinate synthase 1), resulted in decreased circulating arginine levels. Arginase-2 knockout mice were partially protected from BDL-induced renal injury and had less impairment in microvascular function. In human cultured proximal tubular epithelial cells hyperammonemia per se induced upregulation of arginase-2 and markers of tubular cell injury. CONCLUSIONS: We propose that hyperammonemia may contribute to impaired renal arginine metabolism, leading to decreased eNOS activity, impaired microcirculation, tubular cell death, tubulointerstitial nephritis and fibrosis. Genetic deletion of arginase-2 partially restores microcirculation and thereby alleviates tubular injury. We also demonstrate that BDL in mice is an excellent, clinically relevant model to study the renal consequences of HRS. This article is protected by copyright. All rights reserved.}, year = {2018}, eissn = {1527-3350}, pages = {1519-1533}, orcid-numbers = {Varga, Zoltán/0000-0002-2758-0784; Erdélyi, Katalin/0000-0001-8802-1292; Mátyás, Csaba/0000-0001-6095-7611; Németh, Balázs Tamás/0000-0001-7202-8107; Pacher, Pál/0000-0001-7036-8108} } @article{MTMT:3130374, title = {PARP inhibition protects against alcoholic and nonalcoholic steatohepatitis}, url = {https://m2.mtmt.hu/api/publication/3130374}, author = {Mukhopadhyay, P and Horváth, B and Rajesh, M and Varga, Zoltán and Gariani, K and Ryu, D and Cao, Z and Holovac, E and Park, O and Zhou, Z and Xu, MJ and Wang, W and Godlewski, G and Paloczi, J and Németh, Balázs Tamás and Persidsky, Y and Liaudet, L and Haskó, György and Bay, Péter and Boulares, H and Auwerx, J and Gao, B and Pacher, Pál}, doi = {10.1016/j.jhep.2016.10.023}, journal-iso = {J HEPATOL}, journal = {JOURNAL OF HEPATOLOGY}, volume = {66}, unique-id = {3130374}, issn = {0168-8278}, year = {2017}, eissn = {1600-0641}, pages = {589-600}, orcid-numbers = {Varga, Zoltán/0000-0002-2758-0784; Németh, Balázs Tamás/0000-0001-7202-8107; Pacher, Pál/0000-0001-7036-8108} } @article{MTMT:3027326, title = {Urine/Plasma Neutrophil Gelatinase Associated Lipocalin Ratio Is a Sensitive and Specific Marker of Subclinical Acute Kidney Injury in Mice}, url = {https://m2.mtmt.hu/api/publication/3027326}, author = {Kaucsár, Tamás and Godó, Mária and Révész, Csaba and Kovács, Miklós and Mócsai, Attila and Kiss, Norbert and Albert, M and Krenács, Tibor and Szénási, Gábor and Hamar, Péter}, doi = {10.1371/journal.pone.0148043}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {11}, unique-id = {3027326}, issn = {1932-6203}, abstract = {Background Detection of acute kidney injury (AKI) is still a challenge if conventional markers of kidney function are within reference range. We studied the sensitivity and specificity of NGAL as an AKI marker at different degrees of renal ischemia. Methods Male C57BL/6J mice were subjected to 10-, 20- or 30-min unilateral renal ischemia, to control operation or no operation, and AKI was evaluated 1 day later by histology, immunohistochemistry, BUN, creatinine, NGAL (plasma and urine) and renal NGAL mRNA expression. Results A short (10-min) ischemia did not alter BUN or kidney histology, but elevated plasma and urinary NGAL level and renal NGAL mRNA expression although to a much smaller extent than longer ischemia. Surprisingly, control operation elevated plasma NGAL and renal NGAL mRNA expression to a similar extent as 10-min ischemia. Further, the ratio of urine to plasma NGAL was the best parameter to differentiate a 10-min ischemic injury from control operation, while it was similar in the non and control-operated groups. Conclusions These results suggest that urinary NGAL excretion and especially ratio of urine to plasma NGAL are sensitive and specific markers of subclinical acute kidney injury in mice.}, year = {2016}, eissn = {1932-6203}, orcid-numbers = {Kaucsár, Tamás/0000-0003-4460-1265; Révész, Csaba/0000-0001-6016-526X; Kovács, Miklós/0000-0001-9650-3363; Mócsai, Attila/0000-0002-0512-1157; Kiss, Norbert/0000-0002-9947-1755; Krenács, Tibor/0000-0001-9164-065X; Szénási, Gábor/0000-0002-7350-6091; Hamar, Péter/0000-0002-1095-3564} } @article{MTMT:3101389, title = {Diastolic dysfunction in prediabetic male rats: role of mitochondrial oxidative stress}, url = {https://m2.mtmt.hu/api/publication/3101389}, author = {Koncsos, Gábor and Varga, Zoltán and Baranyai, Tamás and Boengler, K and Rohrbach, S and Li, L and Schluter, KD and Schreckenberg, R and Radovits, Tamás and Oláh, Attila and Mátyás, Csaba and Lux, Árpád and Al-Khrasani, Mahmoud and Komlódi, Tímea and Bukosza, Éva Nóra and Máthé, Domokos and Deres, László and Bartekova, M and Rajtik, T and Adameova, A and Szigeti, Krisztián and Hamar, Péter and Helyes, Zsuzsanna and Tretter, László and Pacher, Pál and Merkely, Béla Péter and Giricz, Zoltán and Schulz, R and Ferdinandy, Péter}, doi = {10.1152/ajpheart.00049.2016}, journal-iso = {AM J PHYSIOL HEART C}, journal = {AMERICAN JOURNAL OF PHYSIOLOGY: HEART AND CIRCULATORY PHYSIOLOGY}, volume = {311}, unique-id = {3101389}, issn = {0363-6135}, abstract = {Although incidence and prevalence of prediabetes are increasing, little is known on its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 weeks and treated with a single low dose (20 mg/kg) streptozotocin at week 4. High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose- and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated, however, no molecular sign of fibrosis or cardiac hypertrophy was evidenced. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mTOR or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena which is associated with early changes in mitophagy, cardiac lipid accumulation and elevated oxidative stress, and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria.}, year = {2016}, eissn = {1522-1539}, pages = {H927-H943}, orcid-numbers = {Koncsos, Gábor/0000-0001-5451-8719; Varga, Zoltán/0000-0002-2758-0784; Baranyai, Tamás/0000-0002-9378-8938; Mátyás, Csaba/0000-0001-6095-7611; Lux, Árpád/0000-0002-7048-5619; Al-Khrasani, Mahmoud/0000-0001-8488-3266; Komlódi, Tímea/0000-0001-9876-1411; Hamar, Péter/0000-0002-1095-3564; Tretter, László/0000-0001-5638-2886; Pacher, Pál/0000-0001-7036-8108; Merkely, Béla Péter/0000-0001-6514-0723; Giricz, Zoltán/0000-0003-2036-8665; Ferdinandy, Péter/0000-0002-6424-6806} }