Biology subjects

Campuzano, V.

Publications and source records attributed to Campuzano, V..

5 recordsLinked to original sources

bioRxiv2023

HYPERURICAEMIA DOES NOT INTERFERE WITH AORTOPATHY IN A MURINE MODEL OF MARFAN SYNDROME

Redox stress is involved in the aortic aneurysm pathogenesis in Marfan syndrome (MFS). We recently reported that allopurinol, a recognised inhibitor of XOR, inhibited aortopathy in a mouse model of MFS acting as an antioxidant. Hyperuricaemia is ambiguously associated with cardiovascular injuries as uric acid (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 and cardiopathy 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 ultrasound imaging, aortic wall structure by histopathology, and pNRF2 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.

genetics↗

bioRxiv2023

Dysfunctional Mitochondria in Cardiac Fibers of a Williams-Beuren Syndrome Mouse Model

Williams-Beuren Syndrome (WBS) is a rare neurodevelopmental disorder that, together with a rather characteristic neurocognitive profile, presents a strong cardiovascular phenotype. The cardiovascular features of WBS are mainly related to a gene dosage effect due to hemizygosity of the elastin (ELN) gene; however, the phenotypic variability between WBS patients indicates the presence of important modulators of the clinical impact of elastin deficiency. Recently, two genes within the WBS region have been linked to mitochondrial dysfunction. Numerous cardiovascular diseases are related to mitochondrial dysfunction; therefore, it could be a modulator of the phenotype present in WBS. Here, we analyze mitochondrial function and dynamics in cardiac tissue from a WBS complete deletion (CD) model. Our research reveals that cardiac fiber mitochondria from CD animals have altered mitochondrial dynamics, accompanied by respiratory chain dysfunction with decreased ATP production, reproducing alterations observed in fibroblasts from WBS patients. Our results highlight two major factors; on the one hand, that mitochondrial dysfunction is probably a relevant mechanism underlying several risk factors associated with WBS disease; on the other, the CD murine model mimics the mitochondrial phenotype of WBS and could be a great model for carrying out preclinical tests on drugs targeting the mitochondria.

molecular biology↗

bioRxiv2021

ALLOPURINOL BLOCKS THE FORMATION AND PROGRESSION OF AORTIC ANEURYSM IN A MOUSE MODEL OF MARFAN SYNDROME ACTING AS SCAVENGER OF REACTIVE OXYGEN SPECIES

BackgroundIncreasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy. Methods and ResultsIn aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, fibrotic collagen remodeling, nuclear translocation of pNRF2 and increased 3-nitrotyrosine levels all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression. ConclusionsAllopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients. HIGHLIGHTSO_LIXanthine oxidoreductase (XOR) is upregulated in the aortic aneurysm of Marfan syndrome (MFS) both in patients and young mice. C_LIO_LIAllopurinol halts the formation and progression of aortic aneurysm in MFS mice C_LIO_LIAllopurinol reduces a variety of oxidative stress-associated molecular reactions. C_LIO_LIAllopurinol prevents MFS endothelial-dependent vasodilator dysfunction. C_LIO_LIThe antioxidant action of allopurinol suggests its repositioning for pharmacological use in MFS aortopathy. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/464182v5_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1e6f784org.highwire.dtl.DTLVardef@84075eorg.highwire.dtl.DTLVardef@1ffcb5borg.highwire.dtl.DTLVardef@800503_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2021

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild to moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no available treatments to ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with sub-chronic (10 d) JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiac function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.

animal behavior and cognition↗

bioRxiv2021

Verapamil/Curcumin treatment attenuates the behavioral alterations observed in Williams Syndrome mice by regulation of MAPK pathway and Microglia overexpression

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there currently are not any effective treatments. We investigated the progression of behavioral deficits present in CD (complete deletion) mice, a rodent model of WBS, after chronic treatment with curcumin, verapamil and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism in CD mice. Behavioral improvement correlates with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation with the control of synaptic transmission. Moreover, CD mice showed an increased activated microglia density in different brain regions, which was prevented by treatment. Therefore, results show that treatment prevented behavioral deficits by recovering altered gene expression in cortex of CD mice, reducing activated microglia and normalizing Bdnf expression levels. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice, and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

animal behavior and cognition↗