c6dc42004498c9d19e18b6d7acb02c81 ijms-24-11293.pdf c30be71e5b7549a5f2388d99fdfd9cf9d5f5a4b6 ijms-24-11293.pdf ecc8c9f118afd4711f32fa012a3f27499de068ee23243e1e55a6dfad367a662c ijms-24-11293.pdf Title: Hyperuricaemia Does Not Interfere with Aortopathy in a Murine Model of Marfan Syndrome Subject: Redox stress is involved in the aortic aneurysm pathogenesis in Marfan syndrome (MFS). We recently reported that allopurinol, a xanthine oxidoreductase inhibitor, blocked aortopathy in a MFS mouse model acting as an antioxidant without altering uric acid (UA) plasma levels. Hyperuricaemia is ambiguously associated with cardiovascular injuries as UA, having antioxidant or pro-oxidant properties depending on the concentration and accumulation site. We aimed to evaluate whether hyperuricaemia causes harm or relief in MFS aortopathy pathogenesis. Two-month-old male wild-type (WT) and MFS mice (Fbn1C1041G/+) were injected intraperitoneally for several weeks with potassium oxonate (PO), an inhibitor of uricase (an enzyme that catabolises UA to allantoin). Plasma UA and allantoin levels were measured via several techniques, aortic root diameter and cardiac parameters by ultrasonography, aortic wall structure by histopathology, and pNRF2 and 3-NT levels by immunofluorescence. PO induced a significant increase in UA in blood plasma both in WT and MFS mice, reaching a peak at three and four months of age but decaying at six months. Hyperuricaemic MFS mice showed no change in the characteristic aortic aneurysm progression or aortic wall disarray evidenced by large elastic laminae ruptures. There were no changes in cardiac parameters or the redox stress-induced nuclear translocation of pNRF2 in the aortic tunica media. Altogether, the results suggest that hyperuricaemia interferes neither with aortopathy nor cardiopathy in MFS mice. Keywords: uric acid; aortic aneurysm; Marfan syndrome; allopurinol; oxidative stress; oxonic acid; hyperuricaemia Author: Isaac Rodríguez-Rovira, Angela López-Sainz, Maria Encarnación Palomo-Buitrago, Belen Pérez, Francesc Jiménez-Altayó, Victoria Campuzano and Gustavo Egea Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Jul 11 04:08:25 2023 CEST ModDate: Tue Jul 11 04:47:16 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2511842 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- XWOCXD+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 GFKJOY+VnURWPalladioL Type 1 Custom yes yes no 15 0 YBQPAN+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 MXUVPV+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 VDWEHO+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 CAMXTK+EURM10 Type 1 Builtin yes yes no 71 0 QYNZBG+CMSY10 Type 1 Builtin yes yes no 78 0 IGJHHD+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 92 0 IGJHHE+PalatinoLinotype CID TrueType Identity-H yes yes yes 95 0 IGJHHF+PalatinoLinotype TrueType WinAnsi yes yes no 101 0 IGJHIH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 104 0 IGJKGG+PalatinoLinotype TrueType MacRoman yes yes no 107 0 IGJHHD+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 121 0 IGJHHE+PalatinoLinotype CID TrueType Identity-H yes yes yes 124 0 IGJHHF+PalatinoLinotype TrueType WinAnsi yes yes no 130 0 IGJHIH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 133 0 IGJKGG+PalatinoLinotype TrueType MacRoman yes yes no 136 0 IGJHHD+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 152 0 IGJHHE+PalatinoLinotype CID TrueType Identity-H yes yes yes 155 0 IGJHHF+PalatinoLinotype TrueType WinAnsi yes yes no 161 0 IGJHIH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 164 0 IGJKGG+PalatinoLinotype TrueType MacRoman yes yes no 167 0 IGJHHD+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 182 0 IGJHHE+PalatinoLinotype CID TrueType Identity-H yes yes yes 185 0 IGJHHF+PalatinoLinotype TrueType WinAnsi yes yes no 191 0 IGJHIH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 194 0 IGJHHD+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 208 0 IGJHHE+PalatinoLinotype CID TrueType Identity-H yes yes yes 211 0 IGJHHF+PalatinoLinotype TrueType WinAnsi yes yes no 217 0 IGJHIH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 220 0 IGJKGG+PalatinoLinotype TrueType MacRoman yes yes no 223 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 244 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-02-02 02:39:14 CET RepresentationInformation: ijms-24-11293.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-02-01 18:45:59 CET Size: 2511842 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 498 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Sex Differences in Uric Acid and Allantoin Blood Plasma Levels in MFS Mice Destination: subsection.2.1 Item: Title: Potassium Oxonate Transiently Increased Blood Plasma Levels of Uric Acid Both in WT and MFS Mice Destination: subsection.2.2 Item: Title: Aortopathy in MFS Mice Progressed Regardless of the Potassium Oxonate-Induced Hyperuricaemia Destination: subsection.2.3 Item: Title: The Characteristic Structural Disarray of MFS Aorta Persisted following Potassium Oxonate-Induced Hyperuricaemia Destination: subsection.2.4 Item: Title: Potassium Oxonate-Induced Hyperuricaemia Does Not Modify Redox Stress Markers Changes Occurring in the MFS Aortic Media Destination: subsection.2.5 Item: Title: Blood Pressure Is Not Perturbed by Potassium Oxonate Administration Destination: subsection.2.6 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Chemicals and Reagents Destination: subsection.4.1 Item: Title: Mice, Experimental Design, and Study Approval Destination: subsection.4.2 Item: Title: Uric Acid and Allantoin Analysis in Blood Plasma Destination: subsection.4.3 Item: Title: Echocardiography Destination: subsection.4.4 Item: Title: Histopathology Destination: subsection.4.5 Item: Title: Immunofluorescence Staining Destination: subsection.4.6 Item: Title: Blood Pressure Measurements Destination: subsection.4.7 Item: Title: Statistical Analysis Destination: subsection.4.8 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.A. Info: Title: Hyperuricaemia Does Not Interfere with Aortopathy in a Murine Model of Marfan Syndrome Author: Isaac Rodríguez-Rovira, Angela López-Sainz, Maria Encarnación Palomo-Buitrago, Belen Pérez, Francesc Jiménez-Altayó, Victoria Campuzano and Gustavo Egea Subject: Redox stress is involved in the aortic aneurysm pathogenesis in Marfan syndrome (MFS). We recently reported that allopurinol, a xanthine oxidoreductase inhibitor, blocked aortopathy in a MFS mouse model acting as an antioxidant without altering uric acid (UA) plasma levels. Hyperuricaemia is ambiguously associated with cardiovascular injuries as UA, having antioxidant or pro-oxidant properties depending on the concentration and accumulation site. We aimed to evaluate whether hyperuricaemia causes harm or relief in MFS aortopathy pathogenesis. Two-month-old male wild-type (WT) and MFS mice (Fbn1C1041G/+) were injected intraperitoneally for several weeks with potassium oxonate (PO), an inhibitor of uricase (an enzyme that catabolises UA to allantoin). Plasma UA and allantoin levels were measured via several techniques, aortic root diameter and cardiac parameters by ultrasonography, aortic wall structure by histopathology, and pNRF2 and 3-NT levels by immunofluorescence. PO induced a significant increase in UA in blood plasma both in WT and MFS mice, reaching a peak at three and four months of age but decaying at six months. Hyperuricaemic MFS mice showed no change in the characteristic aortic aneurysm progression or aortic wall disarray evidenced by large elastic laminae ruptures. There were no changes in cardiac parameters or the redox stress-induced nuclear translocation of pNRF2 in the aortic tunica media. Altogether, the results suggest that hyperuricaemia interferes neither with aortopathy nor cardiopathy in MFS mice. 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