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See detailThe tumour suppressor Ras-association domain family protein 1A (RASSF1A) regulates TNF-alpha signalling in cardiomyocytes.
Mohamed, Tamer M. A.; Zi, Min; Prehar, Sukhpal et al

in Cardiovascular research (2014), 103(1), 47-59

AIMS: Tumour necrosis factor-alpha (TNF-alpha) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express the TNF-alpha receptors (TNFRs), the mechanism of ... [more ▼]

AIMS: Tumour necrosis factor-alpha (TNF-alpha) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express the TNF-alpha receptors (TNFRs), the mechanism of TNF-alpha signal transmission is incompletely understood. The aim of this study was to investigate whether the tumour suppressor Ras-association domain family protein 1 isoform A (RASSF1A) modulates TNF-alpha signalling in cardiomyocytes. METHODS AND RESULTS: We used RASSF1A knockout (RASSF1A(-/-)) mice and wild-type (WT) littermates in this study. Acute stimulation with a low dose of TNF-alpha (10 microg/kg iv) increased cardiac contractility and intracellular calcium transients' amplitude in WT mice. In contrast, RASSF1A(-/-) mice showed a blunted contractile response. Mechanistically, RASSF1A was essential in the formation of the TNFR complex (TNFRC), where it functions as an adaptor molecule to facilitate the recruitment of TNFR type 1-associated death domain protein and TNFR-associated factor 2 to form the TNF-alpha receptor complex. In the absence of RASSF1A, signal transmission from the TNF-alpha receptor complex to the downstream effectors, such as cytoplasmic phospholipase A2 and protein kinase A, was attenuated leading to the reduction in the activation of calcium handling molecules, such as L-type Ca(2+) channel and ryanodine receptors. CONCLUSION: Our data indicate an essential role of RASSF1A in regulating TNF-alpha signalling in cardiomyocytes, with RASSF1A being key in the formation of the TNFRC and in signal transmission to the downstream targets. [less ▲]

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See detailEndothelial nitric oxide synthase activity is inhibited by the plasma membrane calcium ATPase in human endothelial cells.
Holton, Marylouisa; Mohamed, Tamer M. A.; Oceandy, Delvac et al

in Cardiovascular research (2010), 87(3), 440-8

AIMS: Nitric oxide (NO) plays a pivotal role in the regulation of cardiovascular physiology. Endothelial NO is mainly produced by the endothelial nitric oxide synthase (eNOS) enzyme. eNOS enzymatic ... [more ▼]

AIMS: Nitric oxide (NO) plays a pivotal role in the regulation of cardiovascular physiology. Endothelial NO is mainly produced by the endothelial nitric oxide synthase (eNOS) enzyme. eNOS enzymatic activity is regulated at several levels, including Ca(2+)/calmodulin binding and the interaction of eNOS with associated proteins. There is emerging evidence indicating a role for the plasma membrane calcium ATPase (PMCA) as a negative regulator of Ca(2+)/calmodulin-dependent signal transduction pathways via its interaction with partner proteins. The aim of our study was to investigate the possibility that the activity of eNOS is regulated through its association with endothelial PMCA. METHODS AND RESULTS: We show here a novel interaction between endogenous eNOS and PMCA in human primary endothelial cells. The interaction domains were located to the region 735-934 of eNOS and the catalytic domain of PMCA. Ectopic expression of PMCA in endothelial cells resulted in an increase in phosphorylation of the residue Thr-495 of endogenous eNOS. However, disruption of the PMCA-eNOS interaction by expression of the PMCA interaction domain significantly reversed the PMCA-mediated effect on eNOS phosphorylation. These results suggest that eNOS activity is negatively regulated via interaction with PMCA. Moreover, NO production by endothelial cells was significantly reduced by ectopic expression of PMCA. CONCLUSION: Our results show strong evidence for a novel functional interaction between endogenous PMCA and eNOS in endothelial cells, suggesting a role for endothelial PMCA as a negative modulator of eNOS activity, and, therefore, NO-dependent signal transduction pathways. [less ▲]

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See detailLigand-dependent activation of ER{beta} lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats.
Jazbutyte, Virginija; Arias-Loza, Paula Anahi; Hu, Kai et al

in Cardiovascular research (2008), 77(4), 774-81

AIMS: The biological effects of oestrogens are mediated by two different oestrogen receptor (ER) subtypes, ERalpha and ERbeta, which might play different, redundant, or opposing roles in cardiovascular ... [more ▼]

AIMS: The biological effects of oestrogens are mediated by two different oestrogen receptor (ER) subtypes, ERalpha and ERbeta, which might play different, redundant, or opposing roles in cardiovascular disease. Previously, we have shown that the selective ERalpha agonist 16alpha-LE2 improves vascular relaxation, attenuates cardiac hypertrophy, and increases cardiac output without lowering elevated blood pressure in spontaneously hypertensive rats (SHR). Because ERbeta-deficient mice exhibit elevated blood pressure and since the ERbeta agonist 8beta-VE2 attenuated hypertension in aldosterone-salt-treated rats, we have now tested the hypothesis that the isotype-selective ERbeta agonist 8beta-VE2 might be capable of lowering elevated blood pressure in ovariectomized SHR. METHODS AND RESULTS: Treatment of ovariectomized SHR with 8beta-VE2 for 12 weeks conferred no uterotrophic effects but lowered elevated systolic blood pressure (-38 +/- 5 mmHg, n = 31, P < 0.001 vs. placebo) as well as peripheral vascular resistance (-31.3 +/- 4.6%, P < 0.001 vs. placebo). 8beta-VE2 enhanced aortic ERbeta expression (+75.7 +/- 7.1%, P < 0.01 vs. placebo), improved NO-dependent vasorelaxation, augmented phosphorylation of the vasodilator-stimulated phosphoprotein in isolated aortic rings (P < 0.05 vs. placebo), increased cardiac output (+20.4 +/- 2.5%, P < 0.01 vs. placebo), and attenuated cardiac hypertrophy (-22.2 +/- 3.2%, p < 0.01 vs. placebo). 8beta-VE2, in contrast to oestradiol, did not enhance cardiac alpha-myosin heavy chain expression. CONCLUSION: Ligand-dependent activation of ERbeta confers blood pressure lowering effects in SHR that are superior to those of 17beta-estradiol or the ERalpha agonist 16alpha-LE2 and attenuates cardiac hypertrophy primarily by a reduction of cardiac afterload without promoting uterine growth. [less ▲]

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See detailThe estrogen receptor-alpha agonist 16alpha-LE2 inhibits cardiac hypertrophy and improves hemodynamic function in estrogen-deficient spontaneously hypertensive rats.
Pelzer, Theo; Jazbutyte, Virginija; Hu, Kai et al

in Cardiovascular research (2005), 67(4), 604-12

OBJECTIVE: Cardiac mass increases with age and with declining estradiol serum levels in postmenopausal women. Although the non-selective estrogen receptor-alpha and -beta agonist 17beta-estradiol ... [more ▼]

OBJECTIVE: Cardiac mass increases with age and with declining estradiol serum levels in postmenopausal women. Although the non-selective estrogen receptor-alpha and -beta agonist 17beta-estradiol attenuates cardiac hypertrophy in animal models and in observational studies, it remains unknown whether activation of a specific estrogen receptor subtype (ERalpha or ERbeta) might give similar or divergent results. Therefore, we analyzed myocardial hypertrophy as well as cardiac function and gene expression in ovariectomized, spontaneously hypertensive rats (SHR) treated with the subtype-selective ERalpha agonist 16alpha-LE2 or 17beta-estradiol. METHODS AND RESULTS: Long-term administration of 16alpha-LE2 or 17beta-estradiol did not affect elevated blood pressure, but both agonists efficiently attenuated cardiac hypertrophy and increased cardiac output, left ventricular stroke volume, papillary muscle strip contractility, and cardiac alpha-myosin heavy chain expression. The observed effects of E2 and 16alpha-LE2 were abrogated by the ER antagonist ZM-182780. Improved left ventricular function upon 16alpha-LE2 treatment was also observed in cardiac MRI studies. In contrast to estradiol and 16alpha-LE2, tamoxifen inhibited cardiac hypertrophy but failed to increase alpha-myosin heavy chain expression and cardiac output. CONCLUSIONS: These results support the hypothesis that activation of ERalpha favorably affects cardiac hypertrophy, myocardial contractility, and gene expression in ovariectomized SHR. Further studies are required to determine whether activation ERbeta mediates redundant or divergent effects. [less ▲]

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See detailCardiac baroreflex function during postural change using non-invasive spontaneous sequence analysis in young men.
Steptoe, Andrew; Vögele, Claus UL

in Cardiovascular Research (1990), 24

STUDY OBJECTIVE: The aim was to assess the value of baroreflex sensitivity estimates calculated from analyses of spontaneous systolic blood pressure and pulse interval sequences derived from continuous ... [more ▼]

STUDY OBJECTIVE: The aim was to assess the value of baroreflex sensitivity estimates calculated from analyses of spontaneous systolic blood pressure and pulse interval sequences derived from continuous non-invasive finger blood pressure recordings during sitting and active standing. DESIGN: Continuous recordings of digital systolic blood pressure and pulse interval were obtained non-invasively using a Finapres FD5 during 5 min trials of sitting and standing. SUBJECTS: Subjects were healthy males aged 19-28, divided into those with "high" normal (n = 18) and "low" normal (n = 17) blood pressure. MEASUREMENTS AND MAIN RESULTS: Recordings were scanned for spontaneous sequences of three or more cardiac cycles over which systolic blood pressure increased progressively in conjunction with prolonged pulse interval, or decreased while pulse interval became shorter. Regressions between blood pressure and pulse interval (r greater than 0.80) provided estimates of cardiac baroreceptor reflex control. Computations were carried out with concurrent blood pressure and pulse interval measurements, and with a delay or lag of one and two cycles between the two variables. Pulse interval was reduced from an average 870.3 ms sitting to 571.3 ms on standing. Mean baroreflex sensitivity while sitting averaged 17.5 ms.mm Hg-1 at a delay of one cycle, failing to 7.65 ms.mm Hg-1 with standing. The decrease in sensitivity was correlated with the change in pulse interval between trials. The number of sequences was also significantly reduced with standing as opposed to sitting. Three cycle sequences were most frequent, with a lesser number of sequences involving 4, 5, and 6 or more cycles. No significant differences between "high" and "low" normal blood pressure groups were observed. CONCLUSIONS: The analysis of spontaneous sequences from non-invasive recordings may provide useful information concerning cardiac baroreflex control in different postural and behavioural states. A lag of one cycle between systolic blood pressure and pulse interval may provide the most representative estimates of baroreflex sensitivity. [less ▲]

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