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Khalid Matrougui

Publications and source records attributed to Khalid Matrougui.

11 recordsLinked to original sources
PubMed2007

Survivin is not only a death encounter but also a survival protein for invading tumor cells.

Cell proliferation and cell death pathways meet at a pivotal crossroad, crucial to maintain normal homeostasis and to eliminate dangerous cells before they start dividing. Survivin (SVV) is an intriguing and fascinating protein at this crossroad that interfaces life and death, through its dual role in facilitating cell division and encountering apoptosis. SVV's prominent expression in essentially all human malignancies, and low or no expression in most normal tissues, suggests that it would be an ideal target for cancer-directed therapy. However, SVV has been recently described as a target for fine tuning by alternative splicing mechanism generating five defined splice variants and a number of other uncharacterized/bizarre isoforms. This diversity indicates that SVV, in addition to its known functions in tumorgenesis, angiogenesis and cardiovascular diseases, might be associated with other unknown functions. Intriguingly, new accumulating evidence from our own work and others, suggest a novel role for SVV in the mechanisms of tumor invasion and metastasis. The SVV pathway has now provided tangible opportunities for targeted, rational cancer therapy. It is therefore an attractive and promising therapeutic target not only for cancer but also for other diseases. Although a number of studies utilizing SVV as an anti-cancer strategy are well underway, further investigation into the exact molecular interactions underpinning its functions is critical for the success of such trials. Impeding development of safe and effective SVV antagonists for clinical use is due to a lack of understanding the molecular mechanisms by which SVV differentially affects apoptosis and cell division in both normal and malignant cells. In this report, in addition to reviewing the SVV known functions, we discuss the newly proposed mechanisms by which SVV might serve as a survival tool for invading tumor cells.

Apoptosis↗
PubMed2006

Mice lacking the gene encoding for MMP-9 and resistance artery reactivity.

OBJECTIVES: To define the link between the deletion of gene encoding for metalloproteinase 9 and resistance artery reactivity, we studied in vitro smooth muscle and endothelial cell function in response to pressure, shear stress, and pharmacological agents. BACKGROUND: Matrix metalloproteinases play a crucial role in the regulation of extracellular matrix turnover and structural artery wall remodeling. METHODS: Resistance arteries were isolated from mice lacking gene encoding for MMP-9 (KO) and their control (WT). Hemodynamic, pharmacology approaches, and Western blot analysis were used in this study. RESULTS: The measurement of blood pressure in vivo was similar in KO and WT mice. Pressure-induced myogenic tone, contractions to angiotensin-II and phenylephrine were similar in both groups. The inhibition of MMP2/9 ((2R)-2-[(4-biphenylylsulfonyl) amino]-3-phenylpropionic acid) significantly decreased myogenic tone in WT and had no effect in KO mice. Relaxation endothelium-dependent (flow-induced- dilation 41.3+/-0.6 vs. 21+/-1.6 at 10 microl/min in KO and WT mice, respectively, P<0.05) and eNOS expression were increased in KO compared to WT mice. The inhibition of eNOS with L-NAME significantly decreased endothelium response to shear stress, which was more pronounced in KO mice resistance arteries (-26.83+/-2.5 vs. -15.84+/-2.3 at 10 microl/min in KO and WT, respectively, P<0.05). However, the relaxation to exogenous nitric oxide-donor was similar in both groups. CONCLUSION: Our study provides evidence of a selective effect of MMP-9 on endothelium function. Thus, MMP-9 gene deletion specifically increased resistance artery dilation endothelium-dependent and eNOS expression. Based on our results, MMP-9 could be a potential therapeutic target in cardiovascular disease associated with resistance arteries dysfunction.

Animals↗
PubMed2006

Hydrogen peroxide acts as relaxing factor in human vascular smooth muscle cells independent of map-kinase and nitric oxide.

We previously showed that hydrogen peroxide (H2O2) induced resistance artery relaxation independent of endothelium. Thus, in this study we investigated the mechanism of relaxation induced by H2O2 on human renal vascular smooth muscle cell (HVSMC). HVSMC were stimulated with H2O2 and/or angiotensin II (Ang II), proline-rich-tyrosine-kinase-2 (PYK2), ERK1/2 MAP-Kinase, and myosin light chain 20 phosphorylation (Lc20) were assessed using Western blot analysis in the presence of potassium channel blockers, MAP-Kinase, and nitric oxide synthesis (NOS) inhibitors. H2O2 increased PYK2 and ERK1/2 phosphorylation, and at the same time decreased Lc20 phosphorylation. AngII increased phosphorylation of PYK2, ERK1/2 and Lc20, whereas, the pretreatment of HVSMC with H2O2 decreased Lc20 phosphorylation induced by AngII. MEK inhibition, decreased ERK1/2 phosphorylation, but had no effect on the inhibition of phosphorylation of Lc20 induced by H2O2. The inhibition of Ca2(+)-dependent K+ channels (BKCa) and NOS did not block the decrease of Lc20 phosphorylation in response to H2O2. On the other hand, pretreatment of HVSMC with 60 mM of KCl, increased rather than decreased Lc20 phosphorylation in response to H2O2. This study shows the evidence that H2O2 acts as a relaxing factor and as an activator of PYK2 and ERK1/2 in Human renal VSMC. The relaxation induced by H2O2 is independent of BKCa, ERK1/2 MAP-Kinase and NOS pathways. The relaxing effect to H2O2 changes to contracting effect when the potassium channels are compromised.

Angiotensin II↗
PubMed2005

Role of SHP-1, Kv.1.2, and cGMP in nitric oxide-induced ERK1/2 MAP kinase dephosphorylation in rat vascular smooth muscle cells.

OBJECTIVE: Nitric oxide (NO) elicits relaxation in vascular smooth muscle cells (VSMC) that is associated with guanylate cyclase (GC) and K(+) channel activation. In this study we determined the mechanisms that lead to ERK1/2 MAP kinase dephosphorylation in response to NO. METHODS: VSMC were treated with the NO donor SNAP or sodium nitroprusside (SNP), and ERK1/2, Src homology (SH) 1 domain-containing protein tyrosine phosphatase (SHP-1), and Kv.1.2 phosphorylation were assessed by immunoprecipitation and Western blot analysis. RESULTS: NO decreased basal ERK1/2 phosphorylation in a dose- and time-dependent manner. NO-induced ERK1/2 dephosphorylation was detected at 1 min and sustained for 30 min. Pre-treatment with the GC inhibitor ODQ or the protein tyrosine phosphatase inhibitor I prevented ERK1/2 dephosphorylation induced by SNAP. The inhibition of protein phosphatase 1A/2A had no effect on ERK1/2 dephosphorylation induced by SNAP. Treatment with cromakalim A, a nonspecific K(+) channel activator, also induced ERK1/2 dephosphorylation, while blockade of Kv.1.2 K(+) channels (AM92016 hydrochloride) prevented NO-induced ERK1/2 dephosphorylation. In addition, SNAP induced SHP-1 phosphorylation, and the Kv.1.2 dephosphorylation increase and SHP-1 phosphorylation was blocked by ODQ or AM92016. The basal interaction between ERK1/2 and SHP-1 was decreased in response to SNAP stimulation. SHP-1 also interacted with Kv.1.2 under basal conditions and participates in Kv.1.2 activation. Using the mouse mesenteric resistance artery, we found that ERK1/2 MAP kinase is involved in regulation of myogenic tone. CONCLUSION: Thus, our study provides the first evidence that NO controls basal ERK1/2 phosphorylation by a signaling cascade that involves a dynamic signaling complex between cGMP, Kv.1.2 and SHP-1.

Animals↗
PubMed2005

Hydrogen peroxide acts as both vasodilator and vasoconstrictor in the control of perfused mouse mesenteric resistance arteries.

BACKGROUND: Hydrogen peroxide (H2O2) plays a key role in the control of resistance artery (RA) tone and is hypothesized as an endothelial-derived hyperpolarizing factor. METHODS: In this study, we investigated the effects of the same concentration of exogenous H2O2 on mouse mesenteric RA tone induced by intraluminal pressure, G-protein coupled receptor activation and KCl. RAs were cannulated in an arteriograph in the absence or presence of vasoconstrictors. RESULTS: RA developed myogenic tone (MT) in response to stepwise pressure increases. Under phenylephrine, H2O2 induced a dose-dependent (1-50 micromol/l) vasodilation with maximum dilation at 50 micromol/l. H2O2 at 50 micromol/l induced a full dilation of RA under MT or contraction by phenylephrine that was independent of nitric oxide synthase, cyclooxygenase, endothelium and potassium channels iberiotoxin and apamin sensitive. The Ca2+ channel inhibitor, nimodipine, significantly blocked MT and also the contraction to phenylephrine and KCl. Under these conditions, H2O2 had no effect on RA diameter. Under KCl, the same concentration of H2O2 induced a potent vasoconstriction. This contraction involved p38 mitogen-activated protein-kinase activation but not ERK1/2. CONCLUSIONS: These findings provide the first evidence showing that the same and low concentrations of H2O2 can act as a relaxing factor but also as a vasoconstrictor under conditions in which hyperpolarization is compromised.

Animals↗
PubMed2004

Involvement of metalloproteinases 2/9 in epidermal growth factor receptor transactivation in pressure-induced myogenic tone in mouse mesenteric resistance arteries.

BACKGROUND: Epidermal growth factor receptor (EGFR) transactivation is a mediator of angiotensin II (Ang II) signaling in cultured vascular smooth muscle cells isolated from large arteries. The present study used mouse mesenteric resistance arteries (MRAs) to investigate the role of EGFR transactivation under pressure-induced myogenic tone (MT). METHODS AND RESULTS: Isolated MRAs were mounted in an arteriograph and stimulated by 25 to 125 mm Hg or with Ang II and KCl. Stepwise increases in pressure resulted in MT development associated with increased EGFR phosphorylation and release of heparin-binding EGF (HB-EGF), a membrane-bound growth factor that is shed on cleavage by metalloproteinases. EGF (50 ng/mL) potentiated MT (59+/-1% to 51+/-0.6% of passive diameter at 75 mm Hg). Pretreatment with the EGFR inhibitors AG1478 (5 micromol/L) or PD153035 (1 micromol/L) significantly decreased MT. However, EGFR inhibitors had no effect on Ang II- and KCl-induced contraction. MT was potentiated by HB-EGF, 50 ng/mL, which is bound to the cell membrane and released on cleavage by metalloproteinases. Neutralizing HB-EGF antibodies or heparin treatment to sequester HB-EGF resulted in significant inhibition of pressure-induced MT. MT increased matrix metalloproteinase (MMP) 2 and MMP-9 gelatinase activity assessed by zymography, and specific MMP 2/9 inhibitors significantly decreased MT. CONCLUSIONS: These novel findings suggest that the mechanism of pressure-induced MT involves metalloproteinases 2/9 activation with subsequent HB-EGF release and EGFR transactivation.

Angiotensin II↗
PubMed2004

Role of tissue kallikrein in response to flow in mouse resistance arteries.

BACKGROUND: Tissue kallikrein, an essential enzyme in the formation of vascular kinins, contributes to flow-dependent dilatation (FDD) in large arteries. We hypothesized that the vascular kinin-kallikrein system may be involved in shear stress signalling in small resistance arteries, which have a key role in the systemic regulation of blood pressure. OBJECTIVE: To investigate the role of the vascular kallikrein-kinin system in mesenteric resistance arteries of mice during acute changes in blood flow. DESIGN: Arteries from wild-type mice (TK) and mice lacking tissue kallikrein (TK) were mounted in an arteriograph for the recording of changes in outer diameter during step increases in flow rate. RESULTS: Responses to phenylephrine, acetylcholine or sodium nitroprusside were not different between the two strains. FDD was significantly reduced in arteries of TK mice compared with that in mesenteric arteries of TK mice exposed to phenylephrine (P = 0.04). FDD was no longer different between TK and TK mice when experiments were performed in the presence of the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (l-NAME; P = 0.26), l-NAME plus diclofenac (P = 0.73), or l-NAME plus diclofenac plus potassium chloride (P = 0.31), indicating that inactivation of tissue kallikrein preferentially affects the contribution of nitric oxide to flow response. However, expression of endothelial NOS was comparable between TK and TK mesenteric arteries. Finally, the bradykinin B2 receptor antagonist, HOE-140, significantly decreased FDD in TK but not in TK arteries (P = 0.03 and P = 0.82, respectively). CONCLUSION: These results demonstrate the specific role of the tissue kallikrein in flow-induced dilatation, which is mediated by nitric oxide and bradykinin B2 receptor activation in resistance arteries.

Acetylcholine↗
PubMed2002

AT2 receptor-mediated relaxation is preserved after long-term AT1 receptor blockade.

Angiotensin II type 2 receptor (AT2R) stimulation may cause vasodilation per se and may contribute to the antihypertensive effect produced by Angiotensin II type 1 receptor (AT1R) antagonists, given that AT1R blockade increases endogenous levels of Ang II, suggesting a physiological role for the unblocked AT2R. Thus, we first directly assessed whether or not there is desensitization to AT2R-mediated vasorelaxation because this is an important consideration, given the raised Ang II levels and the marked desensitization that is known to occur after AT1R stimulation. Second, we examined if AT2R-mediated vasorelaxation is preserved after long-term treatment with the AT1R antagonist candesartan cilexetil. Consecutive concentration-response curves to AT2R stimulation, with either Ang II (with AT1R blockade) or the selective agonist CGP42112, were studied in rat isolated mesenteric resistance arteries mounted in an arteriograph. AT2R stimulation with Ang II induced a concentration-dependent relaxation without desensitization. Similarly, CGP42112 evoked highly reproducible relaxation, which, like Ang II, was abolished by the AT2R antagonist PD123319. By contrast, AT1R-mediated contraction exhibited marked desensitization. In rats treated with candesartan cilexetil (2 mg/kg per day for 2 weeks), AT1R-mediated contraction was abolished, whereas AT2R-mediated relaxation evoked by either Ang II or CGP42112 was highly reproducible, PD123319-sensitive, and of a magnitude similar to that observed in naïve animals. Therefore, this study has provided unequivocal evidence for the reproducible nature of AT2R-mediated vasorelaxation during short-term and long-term AT1R blockade. Such preservation of AT2R function is a prerequisite for the consideration of physiological role(s) of AT2R during AT1R blockade.

Angiotensin II↗
PubMed2001

Selective microvascular dysfunction in mice lacking the gene encoding for desmin.

The intermediate filament desmin has a key role in the integrity and contractility of skeletal and cardiac myocytes. Its absence or aggregation leads to cardiomyopathies. In arteries desmin is distributed heterogeneously; vascular disorders might also occur in its absence. We studied endothelial and muscular functions in arteries from mice lacking desmin (des-/-), compared with control (des+/+). Carotid and mesenteric resistance arteries were mounted in vitro in arteriographs. Desmin was located exclusively in smooth muscle cells. In arteries from des-/- mice, pressure-induced (myogenic) tone was unchanged, but agonist-induced tone decreased in resistance arteries (no change in large arteries). Flow (shear stress)- and acetylcholine-induced, endothelium-dependent dilation, as well as endothelium-independent dilation, were also decreased in resistance arteries. To our knowledge, this is the first study of vascular contractile and dilatory functions in arteries lacking desmin. Although vascular reactivity was normal in large arteries, it decreased strongly in small resistance arteries. Thus, desmin is required in vascular smooth muscle cells and in resistance arteries, for efficient control of vascular tone and consequently for an optimal blood flow supply. This microvascular defect found in the absence of desmin might play a major role in myopathies seen in desmin-related diseases.

Animals↗
PubMedDate not supplied

p38 mitogen-activated protein kinase activation is required for thromboxane- induced contraction in perfused and pressurized rat mesenteric resistance arteries.

Thromboxane A(2) (TxA2) is a potent proaggregating, vasoconstrictor agent produced in many physiological and pathological situations. Although mitogen-activated protein (MAP) kinases [MAPK (ERK1/2 and p38)] have been shown to be activated after endoperoxide/thromboxane receptor (TP) stimulation, no study has investigated their potential role in resistance arteries, especially in physiological conditions of pressure and flow in which the arteries can contract. Thus, responses to TP stimulation by the stable agonist U46619 were studied in isolated rat mesenteric resistance arteries (inner diameter 262 +/- 5 microm) mounted in an arteriograph. Changes in diameter were recorded under physiological levels of flow (90 microl/min) and pressure (50 mm Hg). TP stimulation induced a concentration-dependent contraction (EC(50) value of 1.94 +/- 0.22 x 10(-7) M), without desensitization. U46619-induced contraction was inhibited by calcium entry blockade (nifedipine) and protein kinase C inhibition (GF109203X), but it was not affected by tyrosine kinase inhibition (tyrphostin A25). MAPKK (MEK) inhibition (PD98059) did not alter U46619-dependent contraction, although ERK1/2 MAPK were activated. By contrast, p38 MAPK inhibition (SB203580) dose-dependently inhibited the contraction, and Western blot analysis showed activation of p38 MAPK in arteries contracted with U46619. Activation of p38 MAPK by U46619 was inhibited by nifedipine and in the absence of extracellular calcium. This study brings new insights in the transduction pathway involved in the contractile response of resistance arteries to TxA2/endoperoxide receptor stimulation. This contraction requires p38 MAPK activation, but did not involve ERK1/2 MAPK activation although both were activated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗