TY - JOUR AU - Cziráki, Attila AU - Németh, Zoltán AU - Szabados, Sándor AU - Nagy, Tamás AU - Szántó, Márk AU - Nyakas, Csaba AU - Koller, Ákos TI - Morphological and Functional Remodeling of the Ischemic Heart Correlates with Homocysteine Levels JF - JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE J2 - J CARDIOVASC DEV DIS VL - 10 PY - 2023 IS - 3 PG - 13 SN - 2308-3425 DO - 10.3390/jcdd10030122 UR - https://m2.mtmt.hu/api/publication/33701053 ID - 33701053 N1 - Heart Institute, Medical School and Szentágothai Research Centre, University of Pecs, Pecs, 7624, Hungary Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, 1088, Hungary Eötvös Loránd Research Network, Semmelweis University (ELRN-SU), Cerebrovascular and Neurocognitive Disorders Research Group, Department of Translational Medicine, Faculty of Medicine, Semmelweis University, Budapest, 1094, Hungary Department of Laboratory Medicine, Medical School, University of Pecs, Pecs, 7624, Hungary Research Center for Sports Physiology, Hungarian University of Sports Science, Budapest, 1123, Hungary Department of Physiology, New York Medical College, Valhalla, NY 10595, United States Export Date: 11 October 2023 Correspondence Address: Koller, A.; Department of Morphology and Physiology, Hungary; email: akos.koller@gmail.com AB - Background: Homocysteine (Hcy) is involved in various methylation processes, and its plasma level is increased in cardiac ischemia. Thus, we hypothesized that levels of homocysteine correlate with the morphological and functional remodeling of ischemic hearts. Thus, we aimed to measure the Hcy levels in the plasma and pericardial fluid (PF) and correlate them with morphological and functional changes in the ischemic hearts of humans. Methods: Concentration of total homocysteine (tHcy) and cardiac troponin-I (cTn-I) of plasma and PF were measured in patients undergoing coronary artery bypass graft (CABG) surgery (n = 14). Left-ventricular (LV) end-diastolic diameter (LVED), LV end-systolic diameter (LVES), right atrial, left atrial (LA) area, thickness of interventricular septum (IVS) and posterior wall, LV ejection fraction (LVEF), and right ventricular outflow tract end-diastolic area (RVOT EDA) of CABG and non-cardiac patients (NCP; n = 10) were determined by echocardiography, and LV mass was calculated (cLVM). Results: Positive correlations were found between Hcy levels of plasma and PF, tHcy levels and LVED, LVES and LA, and an inverse correlation was found between tHcy levels and LVEF. cLVM, IVS, and RVOT EDA were higher in CABG with elevated tHcy (>12 µM/L) compared to NCP. In addition, we found a higher cTn-I level in the PF compared to the plasma of CABG patients (0.08 ± 0.02 vs. 0.01 ± 0.003 ng/mL, p < 0.001), which was ~10 fold higher than the normal level. Conclusions: We propose that homocysteine is an important cardiac biomarker and may have an important role in the development of cardiac remodeling and dysfunction in chronic myocardial ischemia in humans. LA - English DB - MTMT ER - TY - JOUR AU - Németh, Zoltán AU - Hildebrandt, Emily AU - Parsa, Nicholas AU - Fleming, Adam B. AU - Wasson, Robert AU - Pittman, Katarina AU - Bell, Xavier AU - Granger, Joey P. AU - Ryan, Michael J. AU - Drummond, Heather A. TI - Epithelial sodium channels in macrophage migration and polarization: role of proinflammatory cytokines TNFα and IFNγ JF - AMERICAN JOURNAL OF PHYSIOLOGY: REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY J2 - AM J PHYSIOL REG I VL - 323 PY - 2022 IS - 5 SP - R763 EP - R775 SN - 0363-6119 DO - 10.1152/ajpregu.00207.2022 UR - https://m2.mtmt.hu/api/publication/33203835 ID - 33203835 AB - Migration of monocytes-macrophages plays an important role in phagocytosis of pathogens and cellular debris in a variety of pathophysiological conditions. Although epithelial Na + channels (ENaCs) are required for normal migratory responses in other cell types, their role in macrophage migration signaling is unknown. To address this possibility, we determined whether ENaC message is present in several peripheral blood monocyte cell populations and tissue-resident macrophages in healthy humans using the Human Protein Atlas database ( www.proteinatlas.org ) and the mouse monocyte cell line RAW 264.7 using RT-PCR. We then determined that selective ENaC inhibition with amiloride inhibited chemotactic migration (∼50%), but not phagocytosis, of the mouse monocyte-macrophage cell line RAW 264.7. Furthermore, we generated a cell line stably expressing an NH 2 -terminal truncated αENaC to interrupt normal channel trafficking and found it suppressed migration. Prolonged exposure (48 h) of RAW 264.7 cells to proinflammatory cytokines interferon γ (IFNγ) and/or tumor necrosis factor α (TNFα) inhibited RAW 264.7 migration and abolished the amiloride (1 µM)-sensitive component of migration, a finding consistent with ENaC downregulation. To determine if proinflammatory cytokines regulate αENaC protein expression, cells were exposed to proinflammatory cytokines IFNγ (10 ng/mL, last 48 h) and TNFα (10 ng/mL, last 24 h). By Western blot analysis, we found whole cell αENaC protein is reduced ≥50%. Immunofluorescence demonstrated heterogeneous αENaC inhibition. Finally, we found that overnight exposure to amiloride stimulated morphological changes and increased polarization marker expression. Our findings suggest that ENaC may be a critical molecule in macrophage migration and polarization. LA - English DB - MTMT ER - TY - JOUR AU - Németh, Zoltán AU - Granger, Joey P. AU - Ryan, Michael J. AU - Drummond, Heather A. TI - Is there a role of proinflammatory cytokines on degenerin‐mediated cerebrovascular function in preeclampsia? JF - PHYSIOLOGICAL REPORTS J2 - PHYSIOL REPORTS VL - 10 PY - 2022 IS - 13 PG - 12 SN - 2051-817X DO - 10.14814/phy2.15376 UR - https://m2.mtmt.hu/api/publication/32950632 ID - 32950632 LA - English DB - MTMT ER - TY - JOUR AU - Németh, Zoltán AU - Hildebrandt, Emily AU - Parsa, Nicholas AU - Crudup, Breland AU - Granger, Joey P. AU - Ryan, Michael J. AU - Drummond, Heather A. TI - Epithelial Sodium Channels in Monocyte‐Macrophage Migration and Regulation by Pro‐inflammatory Cytokines TNFα and IFNγ JF - FASEB JOURNAL J2 - FASEB J VL - 36 PY - 2022 IS - S1 SP - NIH R01 HL1136684 SN - 0892-6638 DO - 10.1096/fasebj.2022.36.S1.R3322 UR - https://m2.mtmt.hu/api/publication/32822771 ID - 32822771 LA - English DB - MTMT ER - TY - JOUR AU - Németh, Zoltán AU - Ryan, Michael J AU - Granger, Joey P AU - Drummond, Heather A TI - Expression of exogenous epithelial sodium channel beta subunit in the mouse middle cerebral artery increases pressure-induced constriction JF - AMERICAN JOURNAL OF HYPERTENSION J2 - AM J HYPERTENS VL - 34 PY - 2021 IS - 11 SP - 1227 EP - 1235 PG - 9 SN - 0895-7061 DO - 10.1093/ajh/hpab098 UR - https://m2.mtmt.hu/api/publication/32081030 ID - 32081030 AB - Pressure-induced constriction (PIC) is inherent to small arteries and arterioles, in which intraluminal pressure-induced vascular smooth muscle cell (VSMC) stretch elicits vasoconstriction. Degenerin (Deg) proteins, such as beta Epithelial Na + Channel (βENaC), have been studied in the PIC response because they are evolutionarily linked to known mechanosensors. While loss of Deg function phenotypes are plentiful, a gain of function phenotype has not been studied. The aim of this study was to determine if expression of exogenous βENaC in the isolated middle cerebral artery (MCA) enhances the PIC response.Isolated MCA segments from female mice (24 wk, n=5) were transfected with enhanced green fluorescent protein-βENaC (EGFP-βENaC) or with EGFP alone, incubated overnight at 37 °C, then studied in a pressure myograph.Mechanical/morphological properties and vasoconstrictor responses to KCl and phenylephrine were identical in EGFP-βENaC-and EGFP MCAs. In contrast, PIC responses were greater in EGFP-βENaC segments with ~2 fold greater peak myogenic tone.These data confirm previous findings that βENaC is critical in the PIC response. These data provide proof-of-concept that upregulating βENaC can enhance PIC responses and lay the foundation to test the hypothesis that inflammation mediated downregulation of βENaC contributes to cerebrovascular dysfunction. LA - English DB - MTMT ER - TY - JOUR AU - Németh, Zoltán AU - Ryan, Michael AU - Granger, Joey AU - Drummond, Heather TI - Upregulation of Epithelial Na + Channel Beta Subunit in Isolated Mouse Middle Cerebral Artery Enhances Pressure‐Induced Constriction JF - FASEB JOURNAL J2 - FASEB J VL - 35 PY - 2021 IS - S1 SN - 0892-6638 DO - 10.1096/fasebj.2021.35.S1.03780 UR - https://m2.mtmt.hu/api/publication/32072499 ID - 32072499 LA - English DB - MTMT ER - TY - JOUR AU - Duncan, Jeremy W. AU - Németh, Zoltán AU - Hildebrandt, Emily AU - Granger, Joey P. AU - Ryan, Michael J. AU - Drummond, Heather A. TI - Interleukin-17 induces hypertension but does not impair cerebrovascular function in pregnant rats JF - PREGNANCY HYPERTENSION J2 - PREGNANCY HYPERTENS VL - 24 PY - 2021 SP - 50 EP - 57 PG - 8 SN - 2210-7789 DO - 10.1016/j.preghy.2021.02.009 UR - https://m2.mtmt.hu/api/publication/31902565 ID - 31902565 LA - English DB - MTMT ER - TY - JOUR AU - Németh, Zoltán AU - Ryan, Michael J. AU - Granger, Joey P. AU - Drummond, Heather A. TI - Pressure‐Induced Constriction of the Middle Cerebral Artery is Abolished in TrpC6 Knockout Mice JF - FASEB JOURNAL J2 - FASEB J VL - 34 PY - 2020 IS - S1 SP - 1 EP - 1 PG - 1 SN - 0892-6638 DO - 10.1096/fasebj.2020.34.s1.05380 UR - https://m2.mtmt.hu/api/publication/31844463 ID - 31844463 LA - English DB - MTMT ER - TY - JOUR AU - Duncan, Jeremy W. AU - Warrington, Junie P. AU - Németh, Zoltán AU - Granger, Joey P. AU - Drummond, Heather A. AU - Ryan, Michael J. TI - Interleukin‐17 Impairs Cerebrovascular Function, Increases Blood‐Brain‐Barrier Permeability, and Induces Cerebral Edema in Pregnant Rats JF - FASEB JOURNAL J2 - FASEB J VL - 34 PY - 2020 IS - S1 SP - 1 EP - 1 PG - 1 SN - 0892-6638 DO - 10.1096/fasebj.2020.34.s1.05801 UR - https://m2.mtmt.hu/api/publication/31844461 ID - 31844461 LA - English DB - MTMT ER - TY - JOUR AU - Németh, Zoltán AU - Hildebrandt, Emily AU - Ryan, Michael J. AU - Granger, Joey P. AU - Drummond, Heather A. TI - Pressure-induced constriction of the middle cerebral artery is abolished in TrpC6 knockout mice JF - AMERICAN JOURNAL OF PHYSIOLOGY: HEART AND CIRCULATORY PHYSIOLOGY J2 - AM J PHYSIOL HEART C VL - 319 PY - 2020 IS - 1 SP - H42 EP - H50 PG - 9 SN - 0363-6135 DO - 10.1152/ajpheart.00126.2020 UR - https://m2.mtmt.hu/api/publication/31453408 ID - 31453408 AB - Pressure-induced constriction (PIC) is an inherent response of small arteries and arterioles in which increases in intraluminal pressure evoke vasoconstriction. It is a critical mechanism of blood flow autoregulation in the kidney and brain. Degenerin (Deg) and transient receptor potential (Trp) protein families have been implicated in transduction of PIC because of evolutionary links to mechanosensing in the nematode and fly. While TrpC6 has been suggested to contribute to PIC signaling, direct supporting evidence is contradictory. Therefore, the aim of this study was to determine the importance of TrpC6 in PIC signaling using a mouse model lacking TrpC6. To address this aim, we evaluated graded pressure (20-90 mmHg). depolarization (4-80 mM KCl)-, and adrenergic receptor (phenylephrine; PE 10(-7)-10(-4) M)-mediated constriction of isolated middle cerebral artery (MCA) segments from 9-wk-old male wild-type (TrpC6(+/+), n = 7) and homozygous null (TrpC6(-/-), n = 9) TrpC6 mice (Jackson Laboratories). Isolated MCA segments were cannulated and pressurized with physiological salt solution using pressure myography (Living Systems). Vasoconstrictor responses to KCl and PE were identical in TrpC6(-/-) and TrpC6(+/+) mice. In contrast, PIC responses were totally abolished in TrpC6(-/-) mice. At 90 mmHg, the calculated myogenic tone was -0.8 +/- 0.5 vs. 10.7 +/- 1.7%, P = 0.0002 in TrpC6(-/-) and TrpC6(+/+) mice, respectively. Additionally, there were no changes in mechanical properties of circumferential wall strain and stress or morphological properties of wall thickness and wall-to-lumen ratio at 50 mmHg between TrpPC6( -/-) and TrpC6(+/+) mice. Although these results demonstrate that TrpC6 is critical for the integrated PIC response, they do not identify whether TrpC6 acts as a mechanosensor or a downstream signaling component.NEW & NOTEWORTHY Pressure-induced, but not agonist-induced, vasoconstriction is abolished in the middle cerebral artery (MCA) of TrpC6 null mice. TrpC6 localization in dissociated cerebral vascular smooth muscle cells is primarily cytoplasmic and not associated with the surface membrane where a mechanoelectrical coupler might be expected. These findings suggest that TrpC6 is required for transduction of pressure-induced constriction in the MCA: however, its role as a mechanoelectrical coupler or downstream signal amplifier remains unresolved. LA - English DB - MTMT ER -