Beaumont, J. (Javier)

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    Association of low GLP-1 with oxidative stress is related to cardiac disease and outcome in patients with type 2 diabetes mellitus: A pilot study
    (Elsevier, 2015) Huerta, A. (Ana); Ravassa, S. (Susana); Barba, J. (Joaquín); Gonzalez, A. (Arantxa); Coma-Canella, I. (Isabel); Beaumont, J. (Javier); López, B. (Begoña); Diez, J. (Javier)
    Oxidative stress (OS) contributes to cardiovascular damage in type 2 diabetes mellitus (T2DM). The peptide glucagon-like peptide-1 (GLP-1) inhibits OS and exerts cardiovascular protective actions. Our aim was to investigate whether cardiac remodeling (CR) and cardiovascular events (CVE) are associated with circulating GLP-1 and biomarkers of OS in T2DM patients. We also studied GLP-1 antioxidant effects in a model of cardiomyocyte lipotoxicity. We examined 72 T2DM patients with no coronary or valve heart disease and 14 nondiabetic subjects. A median of 6 years follow-up information was obtained in 60 patients. Circulating GLP- 1, dipeptidyl peptidase-4 activity, and biomarkers of OS were quantified. In T2DM patients, circulating GLP-1 decreased and OS biomarkers increased, compared with nondiabetics. Plasma GLP-1 was inversely correlated with serum 3-nitrotyrosine in T2DM patients. Patients showing high circulating 3-nitrotyrosine and low GLP- 1 levels exhibited CR and higher risk for CVE, compared to the remaining patients. In palmitate-stimulated HL-1 cardiomyocytes, GLP-1 reduced cytosolic and mitochondrial oxidative stress, increased mitochondrial ATP synthase expression, partially restored mitochondrial membrane permeability and cytochrome c oxidase activity, blunted leakage of creatine to the extracellular medium, and inhibited oxidative damage in total and mitochondrial DNA. These results suggest that T2DM patients with reduced circulating GLP-1 and exacerbated OS may exhibit CR and be at higher risk for CVE. In addition, GLP-1 exerts antioxidant effects in HL-1 palmitate-overloaded cardiomyocytes. It is proposed that therapies aimed to increase GLP-1 may counteract OS, protect from CR, and prevent CVE in patients with T2DM.
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    Identification of a potential cardiac antifibrotic mechanism of torasemide in patients with chronic heart failure
    (Elsevier, 2007) Querejeta, R. (Ramón); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Gonzalez, A. (Arantxa); Larman, M. (Mariano); Beaumont, J. (Javier)
    OBJECTIVES: This study sought to investigate whether torasemide inhibits the enzyme involved in the myocardial extracellular generation of collagen type I molecules (i.e., procollagen type I carboxy-terminal proteinase [PCP]). BACKGROUND: Torasemide has been reported to reduce myocardial fibrosis in patients with chronic heart failure (HF). METHODS: Chronic HF patients received either 10 to 20 mg/day oral torasemide (n = 11) or 20 to 40 mg/day oral furosemide (n = 11) in addition to their standard HF therapy. At baseline and after 8 months from randomization, right septal endomyocardial biopsies were obtained to analyze the expression of PCP by Western blot and the deposition of collagen fibers (collagen volume fraction [CVF]) with an automated image analysis system. The carboxy-terminal propeptide of procollagen type I (PICP) released as a result of the action of PCP on procollagen type I was measured in serum by radioimmunoassay. RESULTS: The ratio of PCP active form to PCP zymogen, an index of PCP activation, decreased (p < 0.05) in torasemide-treated patients and remained unchanged in furosemide-treated patients. A reduction (p < 0.01) in both CVF and PICP was observed in torasemide-treated but not in furosemide-treated patients. Changes in PCP activation were positively correlated (p < 0.001) with changes in CVF and changes in PICP in patients receiving torasemide. CONCLUSIONS: These findings suggest the hypothesis that the ability of torasemide to reduce myocardial fibrosis in chronic HF patients is related to a decreased PCP activation. Further studies are required to ascertain whether PCP may represent a new target for antifibrotic strategies in chronic HF.
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    Vascular oxidant stress: molecular mechanisms and pathophysiological implications
    (Springer Verlag, 2000) Fortuño, A. (Ana); Diez-Martinez, J. (Javier); Fortuño, M.A. (María Antonia); San-Jose, G. (Gorka); Beaumont, J. (Javier); Zalba, G. (Guillermo)
    The term oxidative stress refers to a situation in which cells are exposed to excessive levels of either molecular oxygen or chemical derivatives of oxygen (ie, reactive oxygen species). Three enzyme systems produce reactive oxygen species in the vascular wall: NADH/NADPH oxidase, xanthine oxidoreductase, and endothelial nitric oxide synthase. Among vascular reactive oxygen species superoxide anion plays a critical role in vascular biology because it is the source for many other reactive oxygen species and various vascular cell functions. It is currently thought that increases in oxidant stress, namely excessive production of superoxide anion, are involved in the pathophysiology of endothelial dysfunction that accompanies a number of cardiovascular risk factors including hypercholesterolemia, hypertension and cigarette smoking. On the other hand, vascular oxidant stress plays a pivotal role in the evolution of clinical conditions such as atherosclerosis, diabetes and heart failure.
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    Polymorphisms and promoter overactivity of the p22(phox) gene in vascular smooth muscle cells from spontaneously hypertensive rats
    (American Heart Association, 2001) Fortuño, A. (Ana); Diez-Martinez, J. (Javier); Fortuño, M.A. (María Antonia); San-Jose, G. (Gorka); Beaumont, J. (Javier); Zalba, G. (Guillermo)
    In a previous study, we found that the p22(phox) subunit of the NADH/NADPH oxidase is overexpressed in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHRs) with enhanced vascular production of superoxide anion ((.)O(2)(-)). Thus, we have investigated whether changes in the sequence or activity of the promoter region of p22(phox) gene are present in SHRs. To carry out this analysis, first of all, we characterized the rat gene structure and promoter region for the p22(phox) subunit. The p22(phox) gene spans approximately 10 kb and contains 6 exons and 5 introns. Primer extension analysis indicated the transcriptional start site 100 bp upstream from the translational start site. The immediate promoter region of the p22(phox) gene does not contain a TATA box, but there are a CCAC box and putative recognition sites for nuclear factors, such as SP1, gamma-interferon, and nuclear factor-kappaB. Using reporter-gene transfection analysis, we found that this promoter was functional in VSMCs. Furthermore, we observed that p22(phox) promoter activity was significantly higher in VSMCs from SHRs than from normotensive Wistar-Kyoto rats. In addition, we found that there were 5 polymorphisms in the sequence of p22(phox) promoter between Wistar-Kyoto rats and SHRs and that they were functional. The results obtained in this study provide a tool to explore the mechanisms that regulate the expression of p22(phox) gene in rat VSMCs. Furthermore, our findings show that changes in the sequence of p22(phox) gene promoter and in the degree of activation of VSMCs are responsible for upregulated expression of p22(phox) in SHRs.
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    Biochemical markers of myocardial remodelling in hypertensive heart disease
    (Oxford University Press, 2009) Arias, T. (Teresa); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Zudaire, A. (Amaia); Ravassa, S. (Susana); Gonzalez, A. (Arantxa); Hermida, N. (Nerea); Beaumont, J. (Javier)
    The intricate mechanisms responsible for the structural remodelling of the myocardium that facilitates the evolution to heart failure in hypertensive patients, namely in those with left ventricular hypertrophy, requires from clinicians the utilization of a multibiomarker approach for short-term and long-term stratification as well as prognostication of patients. Biochemical markers may also help to identify patients with no clinical evidence of hypertensive heart disease, and provide information about the need for more aggressive therapy during different stages of the disease, and potentially provide valuable biochemical data for the specialist. Although there is a continuous and complex interplay between biochemical and imaging markers, perhaps their use will also have the potential to modify the medical management of patients with hypertensive heart disease and therapeutic decision-making by tailoring a targeted therapy according to the predominant mechanism of myocardial remodelling. This article will review in brief the most relevant information on a panel of circulating molecules that may accomplish the criteria required to be considered as biochemical markers of the cardiomyocyte and non-cardiomyocyte structural changes that occur in the hypertensive myocardium.
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    Altered cardiac expression of peroxisome proliferator-activated receptor-isoforms in patients with hypertensive heart disease
    (Oxford University Press, 2006) Goikoetxea-Lapresa, M.J. (María José); Querejeta, R. (Ramón); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Gonzalez, A. (Arantxa); Larman, M. (Mariano); Beaumont, J. (Javier)
    OBJECTIVE: To investigate whether cardiac expression of the nuclear peroxisome proliferator-activated receptor alpha (PPARalpha) is altered in patients with hypertensive heart disease (HHD). METHODS: We studied endomyocardial septal biopsies from 24 patients with essential hypertension divided into three groups: 6 without left ventricular hypertrophy (LVH) (HT group), 10 with LVH (LVH group), and 8 with LVH and heart failure (HF) (HF group). The expression of two PPARalpha isoforms (the native active and the truncated inhibitory) was analyzed by Western blot and reverse transcription polymerase chain reaction (RT-PCR), and two PPARalpha target genes were evaluated by RT-PCR. Histomorphological features were evaluated in a second myocardial sample from LVH and HF groups. RESULTS: Whereas the expression of native PPARalpha protein was lower (p<0.05) in LVH and HF groups than in the HT group, truncated PPARalpha protein was overexpressed (p<0.001) in the HF group as compared with LVH and HT groups. The mRNA expression of native and truncated PPARalpha was similar in the three groups of hypertensives. In addition, a progressive decrease (p for trend<0.05) in the two PPARalpha target genes mRNA expression was observed among HT, LVH and HF groups. The amount of truncated PPARalpha protein correlates directly with cardiomyocytes apoptosis and inversely with cardiomyocytes density in patients with HHD. In addition, the expression of truncated PPARalpha protein was directly correlated with left ventricular volumes, and inversely with ejection fraction in all hypertensives. CONCLUSIONS: These findings suggest that post-transcriptional regulation of PPARalpha isoforms is altered in patients with HHD, namely in those developing HF. An excess of the truncated inhibitory isoform may be involved in hypertensive left ventricular failure and remodeling.
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    Oxidative Stress in Arterial Hypertension: Role of NAD(P)H Oxidase
    (American Heart Association, 2001) Moreno, M.U. (María Ujué); Fortuño, A. (Ana); Diez-Martinez, J. (Javier); Fortuño, M.A. (María Antonia); San-Jose, G. (Gorka); Beaumont, J. (Javier); Zalba, G. (Guillermo)
    Increased vascular reactive oxygen species production, especially superoxide anion, contributes significantly in the functional and structural alterations present in hypertension. An enhanced superoxide production causes a diminished NO bioavailability by an oxidative reaction that inactivates NO. Exaggerated superoxide levels and a low NO bioavailability lead to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that the enzyme NAD(P)H oxidase plays a major role as the most important source of superoxide anion in vascular cells. Several experimental observations have shown an enhanced superoxide generation as a result of the activation of vascular NAD(P)H oxidase in hypertension. Although this enzyme responds to stimuli such as vasoactive factors, growth factors, and cytokines, some recent data suggest the existence of a genetic background modulating the expression of its different components. New polymorphisms have been identified in the promoter of the p22(phox) gene, an essential subunit of NAD(P)H oxidase, influencing the activity of this enzyme. Genetic investigations of these polymorphisms will provide novel markers for determination of genetic susceptibility to oxidative stress in hypertension.
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    Association of the peroxisome proliferator-activated receptor α gene L162V polymorphism with stage C heart failure
    (Lippincott, Williams & Wilkins, 2011) Valencia-Serrano, F. (Félix); Beloqui, O. (Óscar); Arias, T. (Teresa); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Gomez-Doblas, J.J. (Juan José); Barba, J. (Joaquín); Teresa, E. (Eduardo) de; Beaumont, J. (Javier); Zalba, G. (Guillermo)
    OBJECTIVE: To analyze whether genetic variants of PPARA are associated with the development of stage C heart failure. METHODS: We analyzed the distribution of the rs1800206, rs4253778 and rs135551 polymorphisms in genomic DNA extracted from peripheral blood cells of 534 patients in different heart failure stages and 63 healthy individuals. The mRNA expression of the peroxisome proliferator-activated receptor (PPAR)α target genes long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and medium-chain acyl-CoA dehydrogenase (MCAD) was measured in myocardial biopsies of a subgroup of stage B and C patients. Functional studies were performed in HL-1 cardiomyocytes. RESULTS: The V162 allele of the rs1800206 polymorphism was more frequent in stage C patients than in stage A and B patients and healthy individuals. Patients with the V162 allele exhibited decreased myocardial LCHAD and MCAD mRNA expression as compared to L162 homozygote patients. In addition, stage C patients exhibited lower myocardial LCHAD and MCAD mRNA expression than stage B patients. Cardiomyocytes transfected with the V162 allele presented decreased PPARα transcriptional activity, LCHAD mRNA expression and ATP production compared to cardiomyocytes transfected with the L162 variant. CONCLUSIONS: These findings suggest that the V162 allele of the human PPARA gene can be a new risk factor in the development of stage C heart failure, likely via depressed cardiac PPARα activity
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    p53-mediated upregulation of BAX gene transcription is not involved in Bax-alpha protein overexpression in the left ventricle of spontaneously hypertensive rats
    (American Heart Association, 1999) Fortuño, A. (Ana); Diez-Martinez, J. (Javier); Ravassa, S. (Susana); Fortuño, M.A. (María Antonia); Beaumont, J. (Javier); Zalba, G. (Guillermo); Elom, E. (E.) De
    An association of increased apoptosis with overexpression of the proapoptotic protein Bax-alpha has been reported in the left ventricle of adult spontaneously hypertensive rats (SHR). Both alterations were corrected in SHR that received long-term treatment with the AT1 antagonist losartan. To gain insight into the regulation of cardiac Bax-alpha protein in genetic hypertension, we investigated the expression of the protein p53 (a BAX gene transcription factor) and BAX mRNA in the left ventricle of 30-week-old Wistar-Kyoto rats (WKY), SHR, and SHR treated with losartan (20 mg. kg-1. d-1) during 14 weeks before death. The expression of p53 and Bax proteins was assessed by Western blot analysis. The expression of BAX mRNA was assessed by Northern blot analysis. The density of apoptotic cells was assessed by direct immunoperoxidase detection of biotin-labeled deoxyuridine nucleotides. Compared with WKY, untreated SHR exhibited increased apoptosis (P<0.05), increased Bax-alpha protein (P<0.05), and similar levels of p53 protein and BAX mRNA. Losartan given long term was associated with the normalization of apoptosis and Bax-alpha protein expression. The expression of BAX mRNA was decreased (P<0. 05) in treated SHR compared with untreated SHR. No changes in the expression of p53 protein were observed in losartan-treated SHR. These results suggest that overexpression of the Bax-alpha protein seen in the left ventricle of adult SHR with increased apoptosis is not related to a p53-mediated upregulation of BAX gene transcription. Our data also suggest that normalization of Bax-alpha protein observed in SHR after long-term blockade of angiotensin II type 1 receptors may be due to the inhibition of BAX gene transcription.
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    Cardiac resynchronization therapy-induced left ventricular reverse remodelling is associated with reduced plasma annexin A5
    (Oxford University Press, 2010) Huerta, A. (Ana); Arias, T. (Teresa); Gavira, J.J. (Juan José); Diez-Martinez, J. (Javier); Zudaire, A. (Amaia); Ravassa, S. (Susana); Macias, A. (Alfonso); Garcia-Bolao, I. (Ignacio); Beaumont, J. (Javier)
    AIMS: Cardiac resynchronization therapy (CRT) diminishes cardiac apoptosis and improves systolic function in heart failure (HF) patients with ventricular dyssynchrony. Plasma annexin A5 (AnxA5), a protein related to cellular damage, is associated with systolic dysfunction. We investigated whether the response to CRT is associated with plasma AnxA5. We also studied AnxA5 overexpression effects in HL-1 cardiomyocytes. METHODS AND RESULTS: AnxA5 ELISA was performed in plasma from 57 patients with HF and ventricular dyssynchrony at baseline and after 1 year of CRT. Patients were categorized as responders if they presented both a reduction in left ventricular (LV) end-systolic volume index (LVESVi) >10% and an increase in LV ejection fraction (LVEF) >10%. HL-1 cells were transfected with human AnxA5 cDNA, and AnxA5, PKC, Akt, p38MAPK, Bcl-2, mitochondrial integrity, caspase-3, and ATP were assessed. At baseline, an increased plasma AnxA5 level was associated with decreased LVEF and increased LVEDVi values (P < 0.05). No differences in baseline AnxA5 were observed between responders and non-responders. After CRT, AnxA5 decreased (P = 0.001) in responders but remained unchanged in non-responders. Final values of AnxA5 were independently associated with LVEF (r = -0.387, P = 0.003) and LVESVi (r = 0.403, P = 0.004) in all patients. Compared with control cells, AnxA5-transfected cells exhibited AnxA5 overexpression, decreased PKC and Akt and increased p38MAPK and Bcl-2 phosphorylation, loss of mitochondrial integrity, caspase-3 activation, and decreased ATP. CONCLUSION: CRT-induced LV reverse remodelling is associated with reduction in plasma AnxA5. The excess of AnxA5 is detrimental for HL-1 cardiomyocytes. Collectively, these data suggest that the beneficial effects of CRT might be related to an AnxA5 decrease.