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Biomedical subjects

R Gros

Publications and source records attributed to R Gros.

10 recordsLinked to original sources
PubMed2001

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice.

We cloned a rat vascular chymase (RVCH) from smooth muscle cells (SMCs) that converts angiotensin I to II and is up-regulated in SMC from spontaneously hypertensive vs. normotensive rats. To determine whether increased activity of RVCH is sufficient to cause hypertension, transgenic mice were generated with targeted conditional expression of RVCH to SMC, with the use of the tetracycline-controlled transactivator (tTA). We confirmed conditional expression of RVCH by mRNA, protein, and chymase activity in the absence, but not in the presence, of dietary doxycycline. The systolic blood pressure (mmHg), measured by carotid artery cannulation at 10-12 weeks of age, was higher in tTA+/RVCH+ mice than in nonbinary transgenic littermates (136 +/- 4 vs. 109 +/- 3) (P < 0.05), as were the diastolic and mean pressures. Hypertension was completely reversed by doxycycline, suggesting a causal link with chymase expression. Medial thickening of mesenteric arteries from tTA+/RVCH+ mice vs. littermates (0.82 +/- 0.1 vs. 0.42 +/- 0.02) (P < 0.05) was associated with increased SMC proliferation, as judged by positive immunoreactivity, with the use of an antibody to the proliferating cell nuclear antigen. These structural changes were prevented by doxycycline. Perfusion myography of mesenteric arteries from tTA+/RVCH+ mice also revealed increased vasoconstriction in response to phenylephrine and impaired metacholine-induced vasodilatation when compared with littermate controls or with the doxycyline-treated group. Our studies suggest that up-regulation of this vascular chymase is sufficient to cause a hypertensive arteriopathy, and that RVCH may be a candidate gene and a therapeutic target in patients with high blood pressure.

Animals↗
PubMed2000

G-Protein-coupled receptor kinase activity in hypertension : increased vascular and lymphocyte G-protein receptor kinase-2 protein expression.

Impaired receptor-stimulated adenylyl cyclase activation has been observed in lymphocytes from hypertensive subjects and has been linked to an increase in lymphocyte G-protein receptor kinase-2 (GRK-2) protein expression. However, whether the increase in lymphocyte GRK-2 reflected an increase in vascular GRK-2 was unknown. Therefore, we compared GRK-2 protein expression in lymphocytes and aortas obtained from normotensive Wistar rats, Wistar-Kyoto rats (WKY), and spontaneously hypertensive rats (SHR) and from aortas of Dahl rats. Impaired beta-adrenergic responsiveness was observed in lymphocytes and vascular tissues obtained from hypertensive SHR (10 and 15 weeks old) but not in those obtained from prehypertensive SHR (5 weeks old). Immunodetectable lymphocyte GRK-2 protein expression was increased in 10-week-old SHR (143+/-10% of the expression in 10-week-old Wistar rats and 131+/-11% of the expression in 10-week-old WKY, n=5 in each group). Immunodetectable vascular smooth muscle cell GRK-2 was comparably increased (169+/-14% of the expression in Wistar rats and 138+/-7% of the expression in WKY, n=5 in each group). Also, in hypertensive Dahl salt-sensitive rats, vascular GRK-2 protein expression was increased (185+/-14% of the expression in Dahl salt-resistant rats, n=5 in each group) compared with Dahl salt-resistant controls. These studies support a generalized defect in vascular GRK-2 protein expression in hypertension, which could be an important factor in the impairment of beta-adrenergic-mediated vasodilation, characteristic of the hypertensive state.

Adenylyl Cyclases↗
PubMed1999

G-protein-coupled receptor kinase expression in hypertension.

In human hypertension we have recently identified an increase in lymphocyte G-protein receptor kinase-2 (GRK-2) protein expression, the key protein regulating the interaction between G-protein-coupled receptors and activation of adenylyl cyclase. However, it was not known whether this increase in GRK-2 protein expression was attributable to regulation at the level of translation. Furthermore, the relationship between extent of GRK-2 expression, receptor activation of adenylyl cyclase, and blood pressure was unclear. We therefore studied lymphocytes from 7 young subjects with borderline hypertension and 14 young normotensive subjects. Immunodetectable GRK-2 protein expression in lymphocytes from subjects with hypertension was increased (155%+/-7% of normotensive subjects; P < .05). In addition, GRK-2 protein expression was positively correlated with blood pressure (r = 0.53; P = .013) and inversely correlated with beta-adrenergic-mediated adenylyl cyclase activity (r = -0.54, P = .012). However, lymphocyte GRK-2 messenger ribonucleic acid (mRNA) content was not altered (110%+/-13% of that observed in normotensive control subjects). Increased GRK-2 protein expression may be an important factor in the impairment of beta-adrenergic-mediated vasodilation, characteristic of the hypertensive state.

Adult↗
PubMed1998

Impaired vasodilator function in hypertension: the role of alterations in receptor-G protein coupling.

Defects in vascular relaxation mechanisms may have an important role in the pathogenesis and maintenance of the elevation in peripheral vascular resistance characteristic of the hypertensive state. Receptor systems that mediate vasorelaxation via elevation of vascular smooth muscle intracellular cAMP concentrations appear to be globally impaired. Recent studies have indicated that this defect may be due to alterations in the transmembrane signaling processes that link receptor activation with the stimulation of adenylyl cyclase. Reduced G-protein function has been reported. However, increased activity of a member of a family of enzymes, the G protein-receptor kinases (GRK), which reduces the efficiency of coupling between the receptor and G protein, may be the key factor accounting for impaired receptor-mediated adenylyl cyclase activation and impaired vasodilator function in the hypertensive state.

Journal Article↗
PubMed1997

G-protein-coupled receptor kinase activity is increased in hypertension.

Impaired vascular beta-adrenergic responsiveness may play an important role in the development and/or maintenance of hypertension. This defect has been associated with an alteration in receptor/guanine nucleotide regulatory protein (G-protein) interactions. However, the locus of this defect remains unclear. G-Protein-coupled receptor kinases (GRKs) phosphorylate serine/threonine residues on G-protein-linked receptors in an agonist-dependent manner. GRK activation mediates reduced receptor responsiveness and impaired receptor/G-protein coupling. To determine whether the impairment in beta-adrenergic response in human hypertension might be associated with altered GRK activity, we studied lymphocytes from younger hypertensive subjects as compared with older and younger normotensive subjects. We assessed GRK activity by rhodopsin phosphorylation and GRK expression by immunoblot. GRK activity was significantly increased in lymphocytes from younger hypertensive subjects and paralleled an increase in GRK-2 (beta ARK-1) protein expression. In contrast, no alterations in cAMP-dependent kinase (A-kinase) activity or GRK-5/6 expression were noted. GRK activity was not increased in lymphocytes from older normotensive subjects who demonstrated a similar impairment in beta-adrenergic-mediated adenylyl cyclase activation. These studies indicate that GRK activity is selectively increased in lymphocytes from hypertensive subjects. The increase in GRK activity may underlie the reduction in beta-adrenergic responsiveness characteristic of the hypertensive state.

Adenylyl Cyclases↗
PubMed1994

Human insulin-mediated enhancement of vascular beta-adrenergic responsiveness.

Insulin may play an important role in the physiological and/or pathophysiological regulation of the cardiovascular system. Defects in insulin secretion and insulin receptor responsiveness have been associated with increased peripheral resistance and hypertension. The mechanisms linking these events remain unclear. To assess the effect of insulin on beta-adrenergic-mediated vasodilation, we examined aortic ring segments obtained from normotensive male Wistar and spontaneously hypertensive rats. Vessels were maximally preconstricted with phenylephrine (3 mumol/L). Relaxation was induced by either isoproterenol (10 mumol/L) or sodium nitroprusside (10 nmol/L), and the relaxant response was followed for 20 minutes. Insulin exposure did not alter phenylephrine-mediated constriction. However, insulin mediated a dose-dependent increase in isoproterenol-induced relaxation, to a maximum of 120 +/- 4% of baseline isoproterenol-mediated relaxation, with an EC50 for insulin of 32 pmol/L in aortic rings from Wistar rats. Insulin exposure also did not alter nitroprusside-mediated relaxation. In contrast to the results obtained in rings from Wistar rats, insulin did not enhance isoproterenol-mediated responses in rings from spontaneously hypertensive rats. Thus, insulin mediates a selective enhancement of vascular beta-adrenergic responsiveness in aortas from normotensive but not hypertensive animals.

Animals↗
PubMed1992

Vascular beta-adrenoceptor-mediated responses in hypertension and ageing in rats.

1. In normotensive Wistar (W) and spontaneously hypertensive (SHR) rats between 5 and 20 weeks of age, there was an age-related increase in blood pressure (r2 = 0.770 and r2 = 0.801 respectively). Except for adrenaline (r2 = 0.979) in SHRs, plasma catecholamines and age were unrelated. 2. In ring segments of thoracic aorta from 5, 10, 15 and 20 week old rats, the respective EC80s (-log M) for phenylephrine (PE)-induced contractions were 8.20 +/- 0.37, 7.96 +/- 0.10, 7.15 +/- 0.12 and 7.12 +/- 0.21 in W and 7.73 +/- 0.13, 7.72 +/- 0.16, 7.37 +/- 0.08 and 7.40 +/- 0.03 in SHR tissues (means +/- SEM; n = 5-7). 3. In PE-preconstricted rings, the respective EC50s (-log M) for isoprenaline (IPNA)-induced relaxation were 7.97 +/- 0.11, 7.74 +/- 0.10, 6.96 +/- 0.19 and 6.57 +/- 0.26 in W and 8.03 +/- 0.24, 7.62 +/- 0.08, 6.88 +/- 0.13 and 6.73 +/- 0.14 in SHR tissues (n = 5-7). 4. In PE-preconstricted rings from 5 and 20 week old rats, a single concentration of IPNA (approximating the respective IPNA EC50s) induced relaxation which was sustained over 2 h in W but not SHR tissues. The SHR:W ratios of the net relaxant responses, at 5 and 20 weeks, were 0.6461 and 0.6167 respectively. 5. Thus, W rats exhibit an age-related loss in both vascular alpha- and beta-adrenoceptor responsiveness which appears unrelated to plasma catecholamines. SHRs also exhibit an age-related loss in vasodilator beta-adrenoceptor responsiveness, which may involve adrenaline-induced desensitization, but appear to maintain vasoconstrictor alpha-adrenoceptor responsiveness. It is proposed that an age-related decline in beta-adrenoceptor responsiveness coupled to maintenance of alpha-adrenoceptor responsiveness may lead to chronic blood pressure elevation, as observed in SHRs, while a parallel decline in both alpha- and beta-adrenoceptor responsiveness, as observed in W rats, may preclude hypertension development.

Aging↗
PubMed1987

[Not Available].

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Balneology↗
PubMed1984

Prostatic carcinoma with concomitant non-Hodgkin lymphoma. Report of 2 cases.

We report 2 cases of adenocarcinoma of the prostate with concomitant non-Hodgkin lymphoma. Only 9 cases of this rare combination have been reported. Both cases are responding well to treatment. The 1st case is 17 years since the diagnosis of adenocarcinoma of prostate and 6 years since the appearance of the lymphoma. The 2nd case is 1 year after being operated on for a gastric lymphoma and 7 months since the diagnosis of adenocarcinoma of prostate was made.

Aged↗