Depósito Académico
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Results
- Association of phagocytic NADPH oxidase activity with hypertensive heart disease: a role for cardiotrophin-1?(2014) Landecho, M.F. (Manuel F.); Moreno, M.U. (María Ujué); Pejenaute, Á. (Ángel); Beloqui, O. (Óscar); Fortuño, A. (Ana); Diez-Martinez, J. (Javier); San-Jose, G. (Gorka); Zalba, G. (Guillermo)Left ventricular hypertrophy (LVH) is an independent marker of mortality in hypertension. Although the mechanisms contributing to LVH are complex, inflammation and oxidative stress may favor its development. We analyzed the association of the phagocytic NADPH oxidase–mediated superoxide anion release and LVH in patients with essential hypertension and the role of cardiotrophin-1 (CT-1) and interleukin-6 (IL-6), cytokines implicated in cardiac growth. Blood pressure, echocardiography data, and serum CT-1 and IL-6 levels were obtained in 140 subjects: 18 normotensives without LVH, 42 hypertensives without LVH, and 80 hypertensives with LVH. The NADPH oxidase–dependent superoxide production was assessed by chemiluminescence in peripheral blood mononuclear cells. Peripheral blood mononuclear cells were stimulated with CT-1 in vitro. Superoxide anion production by peripheral blood mononuclear cells associated with LVH and correlated with the left ventricular mass index. Serum CT-1 and IL-6 levels, which associated with the left ventricular mass index, correlated with superoxide production. Serum CT-1 and IL-6 levels were correlated. CT-1 stimulated NADPH oxidase superoxide production in peripheral blood mononuclear cells, which resulted in an increased release of IL-6. Our results show that superoxide anion production by the phagocytic NADPH oxidase associates with hypertensive heart disease, being significantly enhanced in hypertensive patients with LVH. This may be attributable to the activation of the NADPH oxidase by CT-1 and the subsequent release of IL-6. The phagocytic NADPH oxidase may be a therapeutic target in hypertensive heart disease
- NADPH oxidase-mediated oxidative stress(Mary Ann Liebert, 2005) Moreno, M.U. (María Ujué); Fortuño, A. (Ana); Diez-Martinez, J. (Javier); San-Jose, G. (Gorka); Zalba, G. (Guillermo)Increased vascular production of reactive oxygen species, especially superoxide anion, significantly contributes to the oxidative stress associated with hypertension. An enhanced superoxide production causes an increased inactivation of nitric oxide that diminishes nitric oxide bioavailability, thus contributing to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that NADPH oxidases play a major role as the most important sources of superoxide anion in phagocytic and vascular cells. Several experimental observations have described an enhanced superoxide generation as a result of NADPH oxidase activation in hypertension. Although these enzymes respond to stimuli such as vasoactive factors, growth factors, and cytokines, recent data suggest a significant role of the genetic background in the modulation of the expression of its different components. Several polymorphisms have been identified in the promoter and in the coding region of CYBA, the gene that encodes the essential subunit of the NADPH oxidase p22phox, some of which seem to influence significantly the activity of these enzymes in the context of cardiovascular diseases. Among CYBA polymorphisms, genetic investigations have provided a novel marker, the -930(A/G) polymorphism, which determines the genetic susceptibility of hypertensive patients to oxidative stress.
- Apoptosis en las enfermedades cardiovasculares(Elsevier, 2000) Diez-Martinez, J. (Javier)Apoptosis consists of a distinct form of cell death that displays characteristic alterations in cell morphology and cell fate which are different than death due to oncosis or necrosis. In terms of tissue kinetics, apoptosis may be considered a mechanism that counterbalances the effect of cell proliferation by mitotic division. In fact, deregulated apoptosis has been implicated in the development a wide variety of human diseases. Excessive apoptotic cell death may cause organ atrophy and organ failure. On the other hand, insufficient elimination of redundant cells may lead to organ and tissue structural remodeling. In recent years, apoptosis has become a highly fashionable and competitive area of research. Fortunately, it has not escaped the attention of the cardiovascular community. Sightings of apoptosis have been reported from every corner of cardiovascular medicine ranging from conduction system defects to congestive heart failure, and from atherosclerosis to aneurysms. There is no question that these sightings will eventually be converted into mechanistic etiopathogenic and physiopathological insights and will form the basis for designing new diagnostic modalities and novel therapies.
- Los retos de la hipertensión arterial en el siglo XXI(Sociedad Española de Nefrología, 1999) Diez-Martinez, J. (Javier); Laviades, C. (Concepción)
- El componente renal del riesgo cardiovascular en el paciente hipertenso(Elsevier, 2008) Diez-Martinez, J. (Javier)
- What has changed in the current management of hypertension from the renal point of view?(Elsevier, 2010) Diez-Martinez, J. (Javier)The European Society of Hypertension Task Force on the management of hypertension has recently reappraised the 2007 European guidelines. This reevaluation was based on a number of studies published in the previous 2 years. From a renal point of view, several conclusions of the reevaluation merit consideration. Firstly, the importance of including subclinical renal organ damage when evaluating total cardiovascular risk is reemphasized. Secondly, recommendations for reducing blood pressure to below 130/80 mmHg in diabetic and high-risk hypertensive patients (i.e., patients with renal damage) are critically reappraised, since the expected benefits are not consistently supported by trial evidence. Moreover, in these patients, the J-curve phenomenon may occur, thus compromising renal function. Thirdly, some of the drug combinations recommended in 2007 should be used with extreme precaution in hypertensive patients with renal involvement, especially those interfering with the renin-angiotensin system at different levels.
- Myocardial fibrosis in arterial hypertension(Oxford University Press, 2002) Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Gonzalez, A. (Arantxa)It is now accepted that, in addition to left ventricular hypertrophy, hypertensive heart disease is characterized by alterations in myocardial structure, leading to loss of tissue homogeneity and pathological remodelling. It is time to recognize that, in hypertensive heart disease, it is not only the quantity but also the quality of the myocardium that is responsible for adverse cardiovascular events. The data reviewed here indicate that, in patients with hypertensive heart disease, myocardial fibrosis predisposes to an enhanced risk for diastolic and/or systolic ventricular dysfunction, symptomatic heart failure, ischaemic heart disease and arrhythmias.
- Differential hypertrophic effects of cardiotrophin-1 on adult cardiomyocytes from normotensive and spontaneously hypertensive rats(Elsevier, 2006) Diez-Martinez, J. (Javier); Fortuño, M.A. (María Antonia); Lopez, N. (Natalia)Cardiotrophin-1 (CT-1) produces longitudinal elongation of neonatal cardiomyocytes, but its effects in adult cardiomyocytes are not known. Recent observations indicate that CT-1 may be involved in pressure overload left ventricular hypertrophy (LVH). We investigated whether the hypertrophic effects of CT-1 are different in cardiomyocytes isolated from adult normotensive and spontaneously hypertensive rats (SHR). Hypertrophy was evaluated by planimetry and confocal microscopy, contractile proteins were quantified by Western blotting and real-time RT-PCR, and intracellular pathways were analyzed with specific chemical inhibitors. CT-1 increased c-fos and ANP expression (p<0.01) and cell area (p<0.01) in cardiomyocytes from both rat strains. In Wistar cells, CT-1 augmented cell length (p<0.01) but did not modify either the transverse diameter or cell depth. In SHR cells, CT-1 increased cell length (p<0.05), cell width (p<0.01) and cell depth, augmented the expression of myosin light chain-2v (MLC-2v) and skeletal alpha-actin (p<0.01) and enhanced MLC-2v phosphorylation (p<0.01). The blockade of gp130 or LIFR abolished CT-1-induced growth in the two cell types. All distinct effects observed in cardiomyocytes from SHR were mediated by STAT3. Baseline angiotensinogen expression was higher in SHR cells, and CT-1 induced a 1.7-fold and 3.2-fold increase of angiotensinogen mRNA in cardiomyocytes from Wistar rats and SHR respectively. In addition, AT1 blockade inhibited the specific effects of CT-1 in SHR cells. Finally, ex vivo determinations revealed that adult SHR exhibited enhanced myocardial CT-1 (mRNA and protein, p<0.01), increased cell width (p<0.01) and concentric LVH compared with pre-hypertensive SHR. These findings reveal a specific cell-broadening effect of CT-1 in cardiomyocytes from adult SHR and suggest that the hypertensive phenotype of these cells may influence the hypertrophic effects of CT-1, probably by means of an exaggerated induction of angiotensinogen expression. We suggest that CT-1 might facilitate LVH in genetic hypertension through a cross-talk with the renin-angiotensin system.
- 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.
- Upregulation of myocardial Annexin A5 in hypertensive heart disease: association with systolic dysfunction(Oxford University Press, 2007) Querejeta, R. (Ramón); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Ravassa, S. (Susana); Gonzalez, A. (Arantxa); Larman, M. (Mariano); Beaumont, J. (Javier)AIMS: To investigate whether Annexin A5 (AnxA5) is related to hypertensive heart disease (HHD) and whether this relation is dependent of apoptosis. METHODS AND RESULTS: Hypertensives without cardiac abnormalities (stage A), with left ventricular hypertrophy (LVH) (stage B), and with LVH and clinical manifestations of chronic HF (stage C), were studied. AnxA5 was quantified in endomyocardial biopsies by real time RT-PCR, Western blot, and immunohistochemistry, and apoptosis by DNA fragmentation, caspase-3 activation, and PARP and Bax/Bcl-2 ratios. Plasma AnxA5 was measured by ELISA in samples from the coronary sinus and the antecubital vein. Although AnxA5 mRNA did not change, myocardial and plasma AnxA5 were increased in hypertensives stages B and C compared with normotensives and hypertensives stage A. Myocardial AnxA5 was inversely correlated with parameters assessing systolic function in all hypertensives, this association being independent of apoptosis. Myocardial AnxA5 was directly correlated with plasma AnxA5. Plasma AnxA5 was inversely correlated with systolic function in all hypertensives. CONCLUSION: This cross-sectional study shows that myocardial AnxA5 upregulation is associated with HHD and impairment of systolic function in hypertensive patients, this association being independent of apoptosis. Plasma AnxA5 can be a marker of myocardial AnxA5 upregulation and systolic dysfunction in patients with HHD.