Publications by authors named "Bruno Poirier"

16 Publications

  • Page 1 of 1

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome.

PLoS One 2022 14;17(1):e0257929. Epub 2022 Jan 14.

Diabetes and Cardiovascular Research, Sanofi US Services, Bridgewater, NJ, United States of America.

Aim: Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function.

Methods: 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing adult and aged animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799.

Results: Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in adult and aged animals: in adult animals E/e' was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In aged animals E/e' was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In aged animals, SAR247799 reduced cardiac hypertrophy (g/mm mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In adult animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In aged animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P1 desensitization.

Conclusions: These experimental findings suggest that S1P1 activation with SAR247799 may be considered as a new therapeutic approach for LVH and diastolic dysfunction, major components of HFpEF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257929PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759645PMC
January 2022

High Glucose Activates YAP Signaling to Promote Vascular Inflammation.

Front Physiol 2021 4;12:665994. Epub 2021 Jun 4.

Cardiovascular Research Unit, Sanofi R&D, Chilly-Mazarin, France.

Background And Aims: The YAP/TAZ signaling is known to regulate endothelial activation and vascular inflammation in response to shear stress. Moreover, YAP/TAZ signaling plays a role in the progression of cancers and renal damage associated with diabetes. However, whether YAP/TAZ signaling is also implicated in diabetes-associated vascular complications is not known.

Methods: The effect of high glucose on YAP/TAZ signaling was firstly evaluated on endothelial cells cultured under static conditions or subjected to shear stress (either laminar or oscillatory flow). The impact of diabetes on YAP/TAZ signaling was additionally assessed in mice.

Results: , we found that YAP was dephosphorylated/activated by high glucose in endothelial cells, thus leading to increased endothelial inflammation and monocyte attachment. Moreover, YAP was further activated when high glucose was combined to laminar flow conditions. YAP was also activated by oscillatory flow conditions but, in contrast, high glucose did not exert any additional effect. Interestingly, inhibition of YAP reduced endothelial inflammation and monocyte attachment. Finally, we found that YAP is also activated in the vascular wall of diabetic mice, where inflammatory markers are also increased.

Conclusion: With the current study we demonstrated that YAP signaling is activated by high glucose in endothelial cells and in the vasculature of diabetic mice, and we pinpointed YAP as a regulator of high glucose-mediated endothelial inflammation and monocyte attachment. YAP inhibition may represent a potential therapeutic opportunity to improve diabetes-associated vascular complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2021.665994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213390PMC
June 2021

Apelin improves cardiac function mainly through peripheral vasodilation in a mouse model of dilated cardiomyopathy.

Peptides 2021 08 12;142:170568. Epub 2021 May 12.

Cardiovascular & Metabolism Therapeutic Area, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France. Electronic address:

There is growing evidence that apelin plays a role in the regulation of the cardiovascular system by increasing myocardial contractility and acting as a vasodilator. However, it remains unclear whether apelin improves cardiac contractility in a load-dependent or independent manner in pathological conditions. For this purpose we investigated the cardiovascular effects of apelin in α-actin transgenic mice (mActin-Tg mice), a model of cardiomyopathy. [Pyr]apelin-13 was administered by continuous infusion at 2 mg/kg/d for 3 weeks. Effects on cardiac function were determined by echocardiography and a Pressure-Volume (PV) analysis. mActin-Tg mice showed a dilated cardiomyopathy (DCM) phenotype similar to that encountered in patients expressing the same mutation. Compared to WT animals, mActin-Tg mice displayed cardiac systolic impairment [significant decrease in ejection fraction (EF), cardiac output (CO), and stroke volume (SV)] associated with cardiac ventricular dilation and diastolic dysfunction, characterized by an impairment in mitral flow velocity (E/A) and in deceleration time (DT). Load-independent myocardial contractility was strongly decreased in mActin-Tg mice while total peripheral vascular resistance (TPR) was significantly increased. As compared to vehicle-treated animals, a 3-week treatment with [Pyr]apelin-13 significantly improved EF%, SV, E/A, DT and corrected TPR, with no significant effect on load-independent indices of myocardial contractility, blood pressure and heart rate. In conclusion [Pyr]apelin-13 displayed no intrinsic contractile effect but improved cardiac function in dilated cardiomyopathy mainly by reducing peripheral vascular resistance, with no change in blood pressure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.peptides.2021.170568DOI Listing
August 2021

Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases.

J Med Chem 2021 02 8;64(4):2139-2150. Epub 2021 Feb 8.

Cardio-Vascular and metabolism, Sanofi R&D, 1 rue Pierre Brossolette, Chilly Mazarin 91385, France.

The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (, ). Introduction of suitable spacers and fatty acids led to the identification of single-chain lipidated peptide agonists of RXFP1, with sub-nanomolar activity, high subcutaneous bioavailability, extended half-lives, and efficacy (, ).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01533DOI Listing
February 2021

Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

Br J Clin Pharmacol 2021 05 26;87(5):2303-2320. Epub 2020 Nov 26.

Sanofi US Services, Bridgewater, NJ, USA.

Aims: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P ) agonist designed to activate endothelial S1P and provide endothelial-protective properties, while limiting S1P desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation.

Methods: Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing.

Results: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] -0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI -0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease.

Conclusion: These data provide the first human evidence suggesting endothelial-protective properties of S1P activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247405PMC
May 2021

Lipoprotein(a) Cellular Uptake Ex Vivo and Hepatic Capture In Vivo Is Insensitive to PCSK9 Inhibition With Alirocumab.

JACC Basic Transl Sci 2020 Jun 6;5(6):549-557. Epub 2020 May 6.

Laboratoire Inserm UMR 1188 DéTROI, Université de La Réunion, Sainte Clotilde, France.

Lipoprotein(a) (Lp[a]) is the most common genetically inherited risk factor for cardiovascular disease. Many aspects of Lp(a) metabolism remain unknown. We assessed the uptake of fluorescent Lp(a) in primary human lymphocytes as well as Lp(a) hepatic capture in a mouse model in which endogenous hepatocytes have been ablated and replaced with human ones. Modulation of LDLR expression with the PCSK9 inhibitor alirocumab did not alter the cellular or the hepatic uptake of Lp(a), demonstrating that the LDL receptor is not a major route for Lp(a) plasma clearance. These results have clinical implications because they underpin why statins are not efficient at reducing Lp(a).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacbts.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315184PMC
June 2020

A G protein-biased S1P agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers.

Sci Signal 2020 06 2;13(634). Epub 2020 Jun 2.

Diabetes and Cardiovascular Research, Sanofi US Services, 55 Corporate Drive, Bridgewater, NJ 08807, USA.

Endothelial dysfunction is a hallmark of tissue injury and is believed to initiate the development of vascular diseases. Sphingosine-1 phosphate receptor-1 (S1P) plays fundamental physiological roles in endothelial function and lymphocyte homing. Currently available clinical molecules that target this receptor are desensitizing and are essentially S1P functional antagonists that cause lymphopenia. They are clinically beneficial in autoimmune diseases such as multiple sclerosis. In patients, several side effects of S1P desensitization have been attributed to endothelial damage, suggesting that drugs with the opposite effect, namely, the ability to activate S1P could help to restore endothelial homeostasis. We found and characterized a biased agonist of S1P, SAR247799, which preferentially activated downstream G protein signaling to a greater extent than β-arrestin and internalization signaling pathways. SAR247799 activated S1P on endothelium without causing receptor desensitization and potently activated protection pathways in human endothelial cells. In a pig model of coronary endothelial damage, SAR247799 improved the microvascular hyperemic response without reducing lymphocyte numbers. Similarly, in a rat model of renal ischemia/reperfusion injury, SAR247799 preserved renal structure and function at doses that did not induce S1P-desensitizing effects, such as lymphopenia and lung vascular leakage. In contrast, a clinically used S1P functional antagonist, siponimod, conferred minimal renal protection and desensitized S1P These findings demonstrate that sustained S1P activation can occur pharmacologically without compromising the immune response, providing a new approach to treat diseases associated with endothelial dysfunction and vascular hyperpermeability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scisignal.aax8050DOI Listing
June 2020

Potential Therapeutic Value of Urotensin II Receptor Antagonist in Chronic Kidney Disease and Associated Comorbidities.

J Pharmacol Exp Ther 2020 07 24;374(1):24-37. Epub 2020 Apr 24.

Cardiovascular and Metabolism Therapeutic Area, Sanofi R&D, Chilly-Mazarin, France (M.L.O., V.B., M.P., F.B., P.S., P.B., B.P., P.J.); Preclinical Safety, Sanofi R&D, Chilly-Mazarin, France (J.M.G.);and Chemistry, Sanofi R&D, Chilly-Mazarin, France (F.P., J.M.A., J.P.B.)

Chronic kidney disease (CKD) remains a common disorder, leading to growing health and economic burden without curative treatment. In diabetic patients, CKD may result from a combination of metabolic and nonmetabolic-related factors, with mortality mainly driven by cardiovascular events. The marked overactivity of the urotensinergic system in diabetic patients implicates this vasoactive peptide as a possible contributor to the pathogenesis of renal as well as heart failure. Previous preclinical studies with urotensin II (UII) antagonists in chronic kidney disease were based on simple end points that did not reflect the complex etiology of the disease. Given this, our studies revisited the therapeutic value of UII antagonism in CKD and extensively characterized 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino) cyclohexanecarboxylic acid hydrochloride (SAR101099), a potent, selective, and orally long-acting UII receptor competitive antagonist, inhibiting not only UII but also urotensin-related peptide activities. SR101099 treatment more than halved proteinurea and albumin/creatinine ratio in spontaneously hypertensive stroke-prone (SHR-SP) rats fed with salt/fat diet and Dahl-salt-sensitive rats, respectively, and it halved albuminuria in streptozotocin-induced diabetes rats. Importantly, these effects were accompanied by a decrease in mortality of 50% in SHR-SP and of 35% in the Dahl salt-sensitive rats. SAR101099 was also active on CKD-related cardiovascular pathologies and partly preserved contractile reserve in models of heart failure induced by myocardial infarction or ischemia/reperfusion in rats and pigs, respectively. SAR101099 exhibited a good safety/tolerability profile at all tested doses in clinical phase-I studies. Together, these data suggest that CKD patient selection considering comorbidities together with new stratification modalities should unveil the urotensin antagonists' therapeutic potential. SIGNIFICANCE STATEMENT: Chronic kidney disease (CKD) is a pathology with growing health and economic burden, without curative treatment. For years, the impact of urotensin II receptor (UT) antagonism to treat CKD may have been compromised by available tools or models to deeper characterize the urotensinergic system. New potent, selective, orally long-acting cross-species UT antagonist such as SAR101099 exerting reno- and cardioprotective effects could offer novel therapeutic opportunities. Its preclinical and clinical results suggest that UT antagonism remains an attractive target in CKD on top of current standard of care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.120.265496DOI Listing
July 2020

PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate.

Clin Sci (Lond) 2018 05 31;132(10):1075-1083. Epub 2018 May 31.

Sanofi R&D, Chilly-Mazarin, France.

Therapeutic antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here, we aimed to determine how PCSK9 neutralization modulates Lp(a) levels Six nonhuman primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [H]-leucine, and blood samples were collected sequentially over 48 h. Enrichment of apolipoproteins in [H]-leucine was assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Kinetic parameters were calculated using numerical models with the SAAMII software. Compared with IgG1, alirocumab significantly reduced total cholesterol (TC) (-28%), LDL-C (-67%), Lp(a) (-56%), apolipoprotein B100 (apoB100) (-53%), and apo(a) (-53%). Alirocumab significantly increased the fractional catabolic rate of apoB100 (+29%) but not that of apo(a). Conversely, alirocumab sharply and significantly reduced the production rate (PR) of apo(a) (-42%), but not significantly that of apoB100, compared with IgG1, respectively.In line with the observations made in human hepatocytes, the present kinetic study establishes that PCSK9 neutralization with alirocumab efficiently reduces circulating apoB100 and apo(a) levels by distinct mechanisms: apoB primarily by enhancing its catabolism and apo(a) primarily by lowering its production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/CS20180040DOI Listing
May 2018

The complexity of lipoprotein (a) lowering by PCSK9 monoclonal antibodies.

Clin Sci (Lond) 2017 02;131(4):261-268

Sanofi R&D, Chilly-Mazarin, 91380 France.

Since 2012, clinical trials dedicated to proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition with monoclonal antibodies (mAbs) have unambiguously demonstrated robust reductions not only in low-density lipoprotein (LDL) cholesterol (LDL-C) but also in lipoprotein (a) [Lp(a)] levels. The scientific literature published prior to those studies did not provide any evidence for a link between PCSK9 and Lp(a) metabolism. More recent investigations, either in vitro or in vivo, have attempted to unravel the mechanism(s) by which PCSK9 mAbs reduce circulating Lp(a) levels, with some showing a specific implication of the LDL receptor (LDLR) in Lp(a) clearance whereas others found no significant role for the LDLR in that process. This elusive pathway appears clearly distinct from that of the widely prescribed statins that also enhance LDLR function but do not lower circulating Lp (a) levels in humans. So how does PCSK9 inhibition with mAbs reduce Lp(a)? This still remains to be established.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/CS20160403DOI Listing
February 2017

PCSK9 Modulates the Secretion But Not the Cellular Uptake of Lipoprotein(a) Ex Vivo: An Effect Blunted by Alirocumab.

JACC Basic Transl Sci 2016 Oct;1(6):419-427

Inra UMR 1280, Nantes, France.

To elucidate how the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab modulates lipoprotein(a) [Lp(a)] plasma levels, the authors performed a series of Lp(a) uptake studies in primary human hepatocytes and dermal fibroblasts and measured Lp(a) secretion from human hepatocytes. They found that Lp(a) cellular uptake occurred in a low-density lipoprotein receptor-independent manner. Neither PCSK9 nor alirocumab altered Lp(a) internalization. By contrast, the secretion of apolipoprotein (a) from human hepatocytes was sharply increased by PCSK9, an effect that was reversed by alirocumab. They propose that PCSK9 does not significantly modulate Lp(a) catabolism, but rather enhances the secretion of Lp(a) from liver cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacbts.2016.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753417PMC
October 2016

Long-term blockade of angiotensin AT1 receptors increases survival of obese Zucker rats.

Eur J Pharmacol 2006 Mar 6;534(1-3):271-9. Epub 2006 Mar 6.

Cardiovascular Research Department, Sanofi-Synthelabo Research, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, Hôpital Georges Pompidou, Paris, France.

Despite the well-documented effect of irbesartan, an angiotensin AT1 receptor antagonist, on diabetic nephropathy, its effect on mortality related to multiple metabolic risk factors is unknown. To address this question, obese fa/fa Zucker rats were submitted to a 13-month treatment by irbesartan (30 mg/kg/day p.o.). Vehicle-treated obese fa/fa Zucker rats exhibited an important mortality (72%), which was markedly reduced by irbesartan (22%, P<0.05). Mortality in control lean fa/+ rats attained 12%. Irbesartan diminished the elevation in urinary protein excretion, plasma creatinine and urea nitrogen levels, and reduced the extent of glomerular and tubulo-interstitial lesions together with a reduction of urinary monocyte chemoattractant protein-1 excretion in fa/fa Zucker rats. Irbesartan treatment prevented the rise in plasma total cholesterol, triglycerides and glucose levels, and partially corrected low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio in fa/fa Zucker rats. Therefore, prolonged irbesartan treatment preserves renal function and metabolic profile, and substantially increases survival in obese fa/fa Zucker rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2006.01.032DOI Listing
March 2006

Long-term blockade of angiotensin AT1 receptors increases survival of obese Zucker rats.

Eur J Pharmacol 2006 Mar 6;534(1-3):271-9. Epub 2006 Mar 6.

Cardiovascular Research Department, Sanofi-Synthelabo Research, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, Hôpital Georges Pompidou, Paris, France.

Despite the well-documented effect of irbesartan, an angiotensin AT1 receptor antagonist, on diabetic nephropathy, its effect on mortality related to multiple metabolic risk factors is unknown. To address this question, obese fa/fa Zucker rats were submitted to a 13-month treatment by irbesartan (30 mg/kg/day p.o.). Vehicle-treated obese fa/fa Zucker rats exhibited an important mortality (72%), which was markedly reduced by irbesartan (22%, P<0.05). Mortality in control lean fa/+ rats attained 12%. Irbesartan diminished the elevation in urinary protein excretion, plasma creatinine and urea nitrogen levels, and reduced the extent of glomerular and tubulo-interstitial lesions together with a reduction of urinary monocyte chemoattractant protein-1 excretion in fa/fa Zucker rats. Irbesartan treatment prevented the rise in plasma total cholesterol, triglycerides and glucose levels, and partially corrected low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio in fa/fa Zucker rats. Therefore, prolonged irbesartan treatment preserves renal function and metabolic profile, and substantially increases survival in obese fa/fa Zucker rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2006.01.032DOI Listing
March 2006

High levels of myocardial antioxidant defense in aging nondiabetic normotensive Zucker obese rats.

Am J Physiol Regul Integr Comp Physiol 2004 Apr 11;286(4):R793-800. Epub 2003 Dec 11.

Bicêtre Hospital, Le Kremlin-Bicêtre, France.

Chronic renal failure often induces left ventricular hypertrophy. We assessed whether the heart is affected in the Zucker obese rat, a model of chronic renal failure associated with obesity, glucose intolerance, and insulin resistance without hypertension or hyperglycemia. After systemic blood pressure measurement, the heart, the aorta, and the kidneys were removed from anesthetized 9- and 13-mo-old Zucker obese and lean control male rats (n = 33, n = 24, n = 25, and n = 21, respectively). Determination of left ventricular geometry, quantification of myocardium collagen density, and measurement of heart antioxidant enzyme activity were made, as well as aorta and kidney parameters. Mean blood pressure remained at a normal range whatever the age and group considered. Whereas kidney structure and function were severely impaired, no sign of myocardial infarction or inflammatory process was noticed. A moderate left ventricular hypertrophy was observed in 13-mo-old obese rats. While heart malondialdehyde was stable with age and among groups, antioxidant enzyme activity was higher in obese rats. In conclusion, in the absence of hypertensive or hyperglycemic disorders, the heat seems to display a sufficient line of defense against oxidative stress during the development of cardiac hypertrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpregu.00521.2002DOI Listing
April 2004

Inhibition of IGF-I-induced Erk 1 and 2 activation and mitogenesis in mesangial cells by bradykinin.

Kidney Int 2002 Aug;62(2):412-21

INSERM U388, Institut Louis Bugnard, CHU Rangueil, Toulouse, France.

Background: The beneficial effects of therapeutic angiotensin-converting enzyme (ACE) inhibitor treatment against the worsening of glomerulosclerosis during the course of diabetic nephropathy have been widely documented. ACE inhibitors inhibit both angiotensin II formation and bradykinin (BK) degradation, thereby reducing angiotensin II type 1 (AT1) receptor activity and favoring B2-kinin receptor (B2 receptor) activation. Since the involvement of growth factors such as insulin-like growth factor (IGF-I) has been implicated in the early steps of diabetic nephropathy, we investigated the effect of BK on Erk 1 and 2 activation and cell proliferation by IGF-I.

Methods: The activation of Erk 1 and 2 in mesangial cells (MCs) and isolated glomeruli (IG) was investigated by immunoprecipitation and Western blotting during activation of the IGF-I receptor in the presence or absence of BK and of protein kinase C (PKC), tyrosine-kinase and phosphatase selective inhibitors. Mesangial cell proliferation was assessed in vitro by cell counting.

Results: In untreated MCs and IG, when added separately, BK and IGF-I both activated Erk 1 and 2. In contrast, in MCs and IG pretreated with BK, the IGF-I-induced Erk 1 and 2 activation was dose-dependently reduced. The inhibitory effect of BK on IGF-I-induced activation of Erk 1 and 2 was completely abolished by addition of a B2 antagonist, by chelation of intracellular calcium and by tyrosine phosphatase inhibition. Additionally, BK reduced MC proliferation induced by IGF-I.

Conclusions: A new inhibitory pathway of the early steps of IGF-I signaling by the B2 receptor is found both in cultured MCs and in IG, which involves a calcium-dependent tyrosine phosphatase activity. Recruitment of this mechanism may account for the beneficial effects of ACE inhibitor treatment on glomerulosclerosis associated with diabetic nephropathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1046/j.1523-1755.2002.00475.xDOI Listing
August 2002

Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice.

J Clin Invest 2002 Mar;109(6):745-53

Center for Molecular Medicine and Department of Medicine, Karolinska Institute, SE-171 76 Stockholm, Sweden.

Atherosclerosis is characterized by vascular inflammation and associated with systemic and local immune responses to oxidized LDL (oxLDL) and other antigens. Since immunization with oxLDL reduces atherosclerosis, we hypothesized that the disease might be associated with development of protective immunity. Here we show that spleen-associated immune activity protects against atherosclerosis. Splenectomy dramatically aggravated atherosclerosis in hypercholesterolemic apoE knockout (apoE degrees ) mice. Transfer of spleen cells from atherosclerotic apoE degrees mice significantly reduced disease development in young apoE degrees mice. To identify the protective subset, donor spleen cells were divided into B and T cells by immunomagnetic separation before transfer. Protection was conferred by B cells, which reduced disease in splenectomized apoE degrees mice to one-fourth of that in splenectomized apoE degrees controls. Protection could also be demonstrated in intact, nonsplenectomized mice and was associated with an increase in antibody titers to oxLDL. Fewer CD4(+) T cells were found in lesions of protected mice, suggesting a role for T-B cell cooperation. These results demonstrate that B cell-associated protective immunity develops during atherosclerosis and reduces disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI7272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC150903PMC
March 2002
-->