Eric Thorin - Academia.edu (original) (raw)

Papers by Eric Thorin

Circulation, 2014

Introduction: Exercise training in patients who have suffered an acute coronary syndrome is assoc... more Introduction: Exercise training in patients who have suffered an acute coronary syndrome is associated with a significant reduction in mortality and cardiovascular events. Moderate intensity continuous exercise training (MICET) is currently recommended. Recently, high-intensity interval training (HIIT), that utilizes short bursts of very intense efforts interspersed with periods of recovery, has been explored as an alternative to MICET. The safety aspects of HIIT in patients post acute coronary syndrome (ACS) have been poorly described. Methods: Thirty-seven low-risk patients post ACS (65% STEMI, fully revascularized, EF > 40%, age 61±9 years, 8 women) were randomized 4 weeks to 6 months post ACS; to 12 to 18 weeks of 2-3 sessions/week (total: 36 sessions) of isocaloric MICET or HIIT on cycle ergometer. VO2peak and maximal aerobic power (MAP) were determined using maximal cardiopulmonary exercise test (CPET) on cycle ergometer and continuous ECG and BP were monitored every 2 min....

International Journal of Molecular Sciences, 2021

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible... more Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in whic...

Aging, 2019

Elimination of senescent cells (SnC) is anti-atherogenic, but the specific contribution of senesc... more Elimination of senescent cells (SnC) is anti-atherogenic, but the specific contribution of senescent vascular endothelial cells (EC) is unknown. We inactivated angiopoietin like-2 (angptl2), a marker of SnEC and a proatherogenic cytokine in LDLr-/-, hApoB100 +/+ atherosclerotic (ATX) mice. Three months after a single vascular delivery of a small hairpin (sh)Angptl2 in 3-month old ATX mice using an adeno-associated virus serotype 1 (AAV1), aortic atheroma plaque progression was slowed by 58% (p<0.0001). In the native aortic endothelium, angptl2 expression was decreased by 80%, in association with a reduced expression of p21, a cyclin-dependent kinase inhibitor overexpressed in growth-arrested SnC. Endothelial activation was reduced (lower Icam-1, Il-1β and Mcp-1 expression), decreasing monocyte Cd68 expression in the endothelium. One week post-injection, the ratio Bax/Bcl2 increased in the endothelium only, suggesting that angptl2 + /p21 + SnEC were eliminated by apoptosis. Four weeks post-injection, the endothelial progenitor marker Cd34 increased, suggesting endothelial repair. In arteries of atherosclerotic patients, we observed a strong correlation between p21 and ANGPTL2 (r=0.727, p=0.0002) confirming the clinical significance of angptl2-associated senescence. Our data suggest that therapeutic down-regulation of vascular angptl2 leads to the clearance of SnEC by apoptosis, stimulates endothelial repair and reduces atherosclerosis.

American Journal of Physiology-Heart and Circulatory Physiology, 2018

Aging is a modern concept: human life expectancy has more than doubled in less than 150 yr in Wes... more Aging is a modern concept: human life expectancy has more than doubled in less than 150 yr in Western countries. Longer life span, however, reveals age-related diseases, including cerebrovascular diseases. The vascular system is a prime target of aging: the “wear and tear” of large elastic arteries exposed to a lifelong pulsatile pressure causes arterial stiffening by fragmentation of elastin fibers and replacement by stiffer collagen. This arterial stiffening increases in return the amplitude of the pulse pressure (PP), its wave penetrating deeper into the microcirculation of low-resistance, high-flow organs such as the brain. Several studies have associated peripheral arterial stiffness responsible for the sustained increase in PP, with brain microvascular diseases such as cerebral small vessel disease, cortical gray matter thinning, white matter atrophy, and cognitive dysfunction in older individuals and prematurely in hypertensive and diabetic patients. The rarefaction of white ...

Circulation, Jan 19, 2018

American journal of hypertension, 2017

Angiopoietin-like-2 (ANGPTL2) is a secreted proinflammatory glycoprotein that promotes endothelia... more Angiopoietin-like-2 (ANGPTL2) is a secreted proinflammatory glycoprotein that promotes endothelial dysfunction, atherosclerosis, and cardiovascular disease (CVD). Circulating ANGPTL2 is increased in chronic kidney disease (CKD), where the risk of CVD is amplified. The objectives of the present study were to (i) examine whether kidney transplantation (KTx) reduces ANGPTL2 levels, (ii) identify the determinants of ANGPTL2 after KTx, (iii) study the association of ANGPTL2 with aortic stiffness, and (iv) assess the impact of ANGPTL2 on mortality after KTx. In 75 patients, serum ANGPTL2 levels were measured at baseline and 3 months after KTx. Aortic stiffness was determined by carotid-femoral pulse wave velocity, glomerular filtration rate was estimated by CKD-EPI formula, and serum cytokines and endothlin-1 levels were determined 3 months after KTx. Survival analysis was performed using Kaplan-Meier and Cox regression after a median follow-up of 90 months. After 3 months of KTx, ANGPTL2...

PloS one, 2016

Pro-inflammatory angiopoietin-like 2 (angptl2) promotes endothelial dysfunction in mice and circu... more Pro-inflammatory angiopoietin-like 2 (angptl2) promotes endothelial dysfunction in mice and circulating angptl2 is higher in patients with cardiovascular diseases. We previously reported that a single bout of physical exercise was able to reduce angptl2 levels in coronary patients. We hypothesized that chronic exercise would reduce angptl2 in patients with post-acute coronary syndrome (ACS) and endothelial dysfunction. Post-ACS patients (n = 40, 10 women) were enrolled in a 3-month exercise-based prevention program. Plasma angptl2, hs-CRP, and endothelial function assessed by scintigraphic forearm blood flow, were measured before and at the end of the study. Exercise increased VO2peak by 10% (p<0.05), but did not significantly affect endothelial function, in both men and women. In contrast, exercise reduced angptl2 levels only in men (-26±7%, p<0.05), but unexpectedly not in women (+30±16%), despite similar initial levels in both groups. Exercise reduced hs-CRP levels in men b...

Diabetologia, 2016

Aims/hypothesis A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk f... more Aims/hypothesis A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk factor for developing diabetes and is associated with insulin resistance and atherosclerosis. In this work, we have examined the impact of serum ANGPTL2 on improving cardiovascular (CV) risk stratification in patients with type 2 diabetes. Methods A prospective, monocentric cohort of consecutive type 2 diabetes patients (the SURDIAGENE cohort; total of 1353 type 2 diabetes patients; 58% men, mean ± SD age 64 ± 11 years) was followed for a median of 6.0 years for death as primary endpoint and major adverse CV events (MACE; i.e. CV death, myocardial infarction or stroke) as a secondary endpoint. Patients with end-stage renal disease, defined as a requirement for dialysis or a history of kidney transplantation, Eric Thorin and Samy Hadjadj contributed equally to this study.

American journal of physiology. Heart and circulatory physiology, Jan 5, 2016

While heart rate reduction (HRR) is a target for the management of patients with heart disease; c... more While heart rate reduction (HRR) is a target for the management of patients with heart disease; contradictory results were reported using ivabradine, which selectively inhibits the pacemaker If current, vs. β-blockers like metoprolol. This study aimed at testing whether similar HRR with ivabradine vs. metoprolol differentially modulates cardiac energy substrate metabolism, a factor determinant for cardiac function, in a mouse model of dyslipidemia (hApoB(+/+);LDLR(-/-)). Following a longitudinal study design, we used 3- and 6-month-old mice, untreated or treated for 3 months with ivabradine or metoprolol. Cardiac function was evaluated in vivo, and ex vivo in working hearts perfused with (13)C-labeled substrates to assess substrate fluxes through energy metabolic pathways. Compared to 3-month-old, 6-month-old dyslipidemic mice had similar cardiac hemodynamics in vivo, but impaired (P<0.001) contractile function (aortic flow:-45%; cardiac output:-34%; stroke volume:-35%) and glyco...

PloS one, 2016

Exercise is an effective approach for primary and secondary prevention of cardiovascular diseases... more Exercise is an effective approach for primary and secondary prevention of cardiovascular diseases (CVD) and loss of muscular mass and function. Its benefits are widely documented but incompletely characterized. It has been reported that exercise can induce changes in the expression of antioxidant enzymes including Sod2, Trx1, Prdx3 and Gpx1 and limits the rise in oxidative stress commonly associated with CVD. These enzymes can be subjected to epigenetic regulation, such as DNA methylation, in response to environmental cues. The aim of our study was to determine whether in the early stages of atherogenesis, in young severely dyslipidemic mice lacking LDL receptors and overexpressing human ApoB100 (LDLR-/-; hApoB+/+), exercise regulates differentially the expression of antioxidant enzymes by DNA methylation in the skeletal muscles that consume high levels of oxygen and thus generate high levels of reactive oxygen species. Expression of Sod2, Txr1, Prdx3 and Gpx1 was altered by 3 month...

PloS one, 2016

DNA methylation is believed to regulate gene expression during adulthood in response to the const... more DNA methylation is believed to regulate gene expression during adulthood in response to the constant changes in environment. The methylome is therefore proposed to be a biomarker of health through age. ANGPTL2 is a circulating pro-inflammatory protein that increases with age and prematurely in patients with coronary artery diseases; integrating the methylation pattern of the promoter may help differentiate age- vs. disease-related change in its expression. We believe that in a pro-inflammatory environment, ANGPTL2 is differentially methylated, regulating ANGPTL2 expression. To test this hypothesis we investigated the changes in promoter methylation of ANGPTL2 gene in leukocytes from patients suffering from post-acute coronary syndrome (ACS). DNA was extracted from circulating leukocytes of post-ACS patients with cardiovascular risk factors and from healthy young and age-matched controls. Methylation sites (CpGs) found in the ANGPTL2 gene were targeted for specific DNA methylation qu...

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, Jan 28, 2016

Arterial blood pressure is oscillatory; whether pulse pressure (PP) regulates cerebral artery myo... more Arterial blood pressure is oscillatory; whether pulse pressure (PP) regulates cerebral artery myogenic tone (MT) and endothelial function is currently unknown. To test the impact of PP on MT and dilation to flow (FMD) or to acetylcholine (Ach), isolated pressurized mouse posterior cerebral arteries were subjected to either static pressure (SP) or a physiological PP (amplitude: 30 mm Hg; frequency: 550 bpm). Under PP, MT was significantly higher than in SP conditions (p < 0.05) and was not affected by eNOS inhibition. In contrast, under SP, eNOS inhibition increased (p < 0.05) MT to levels observed under PP, suggesting that PP may inhibit eNOS. At a shear stress of 20 dyn/cm(2), FMD was lower (p < 0.05) under SP than PP. Under SP, eNOS-dependent [Formula: see text] production contributed to FMD, while under PP, eNOS-dependent NO was responsible for FMD, indicating that PP favours eNOS coupling. Differences in FMD between pressure conditions were abolished after NOX2 inhibiti...

Applied Physiology, Nutrition, and Metabolism, 2016

Cardiovascular risk factors are known to exacerbate high-saturated fatty acid meal (HSFAM)-induce... more Cardiovascular risk factors are known to exacerbate high-saturated fatty acid meal (HSFAM)-induced endothelial dysfunction, but the influence of subclinical metabolic dysregulations and the acute impact of a single mixed Mediterranean-type meal (MMM) remains unknown. Thus, this study has the objective to evaluate the metabolic and vascular effect of such meals in healthy subjects with or without subclinical fasting metabolic dysregulations. Twenty-eight healthy males without overt cardiovascular risk factors randomly ingested 1 of 2 isocaloric meals on separate days. Plasma metabolic markers, fatty acid (FA) profile, and endothelial function (flow-mediated dilatation; FMD) were assessed at baseline and 2 and 4 h after meal ingestion. Unsupervised hierarchical clustering identified 2 subgroups of participants (n = 11 and 17) differing by their baseline metabolic profiles. The MMM did not significantly alter postprandial endothelial function in all subjects, irrespective of baseline m...

Circulation, Nov 25, 2014

Introduction: Angiopoietin-like 2 (angptl2) is a circulating pro-inflammatory and pro-oxidative p... more Introduction: Angiopoietin-like 2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein that induces endothelial dysfunction in mice. Plasma angptl2 levels are increased in diabetic or atherosclerotic patients, while a lifestyle intervention has been shown to decrease angptl2 expression in overweight, but otherwise healthy men. Whether angptl2 levels are sensitive to exercise in CAD patients is unknown. Hypothesis: Exercise training reduces angptl2 levels in patients with CAD and endothelial dysfunction. Methods: Stable and optimally treated CAD patients (n=31, 60±2 y/o, 7 females) were enrolled in a 3-month exercise-based prevention program at the Montreal Heart Institute. Blood samples were collected before and at the end of the study to measure plasma levels of angptl2 (ELISA) and of hs-CRP. Endothelial function was assessed by measuring the ratio of the slope of the nuclear tracer Myoview activity-time in the right to the left arm. A ratio lower than 3.55 is indicative of endothelial dysfunction. Data are mean±SEM. Results: Exercise training was associated with a 11% increase in maximal cardiopulmonary capacity (VO2max; p=0.003). Endothelial function was not affected by exercise (from 3.41±0.25 to 3.58±0.26; p=0.455), but plasma levels of angptl2 were significantly decreased by 32% (from 3.4±0.7 to 2.3±0.4 ng/ml; p=0.020), while hs-CRP levels were unaffected (from 2.2±0.5 to 1.5±0.2 mg/l; p=0.155). Levels of angptl2 (but not of hs-CRP) were negatively correlated with VO2max (p=0.0471, r=0.257): the lower angptl2, the fitter the patient. In addition, levels of angptl2 (but not of hs-CRP) were negatively correlated with endothelial function (p=0.0217, r=0.304): the lower angptl2, the better the endothelial function. Importantly, exercise training was associated with a reduction in angptl2 levels (from 4.3±1.2 to 2.5±0.6 ng/ml; p=0.011, n=18) only among individuals with endothelial dysfunction at baseline, but not in patients with normal endothelial function (from 2.2±0.4 to 1.7±0.4 ng/ml; p=0.350, n=11). Conclusions: In CAD patients with endothelial dysfunction, angptl2 levels are sensitive to exercise training. Low levels of angptl2 may reflect good cardiopulmonary fitness and endothelial function.

Journal of the American Heart Association, Jan 10, 2013

Angiopoietin like-2 (angptl2), a proinflammatory protein, is overexpressed in endothelial cells (... more Angiopoietin like-2 (angptl2), a proinflammatory protein, is overexpressed in endothelial cells (ECs) from patients with coronary artery disease (CAD). Whether angptl2 contributes to atherogenesis is unknown. We tested the hypothesis that angptl2 promotes inflammation and leukocyte adhesion onto ECs, thereby accelerating atherogenesis in preatherosclerotic dyslipidemic mice. In ECs freshly isolated from the aorta, basal expression of TNF-α and IL-6 mRNA was higher in 3-month-old severely dyslipidemic mice (LDLr(-/-); hApoB100(+/+) [ATX]) than in control healthy wild-type (WT) mice (P<0.05) and was increased in both groups by exogenous angptl2 (100 nmol/L). Angptl2 stimulated the adhesion of leukocytes ex vivo on the native aortic endothelium of ATX, but not WT mice, in association with higher expression of ICAM-1 and P-selectin in ECs (P<0.05). Antibodies against these endothelial adhesion molecules prevented leukocyte adhesion. Intravenous administration of angptl2 for 1 mont...

AJP: Heart and Circulatory Physiology, 2015

Angiopoietin like-2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein, but it... more Angiopoietin like-2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein, but its role in regulating cerebral endothelial function remains unknown. We hypothesized that in mice knockdown (KD) of angptl2, cerebral endothelial function would be protected against ANG II-induced damage. Subcutaneous infusion of ANG II (200 ng·kg−1·min−1, n = 15) or saline ( n = 15) was performed in 20-wk-old angptl2 KD mice and wild-type (WT) littermates for 14 days. In saline-treated KD and WT mice, the amplitude and the sensitivity of ACh-induced dilations of isolated cerebral arteries were similar. However, while endothelial nitric oxide (NO) synthase (eNOS)-derived O2−/H2O2 contributed to dilation in WT mice, eNOS-derived NO ( P < 0.05) was involved in KD mice. ANG II induced cerebral endothelial dysfunction only in WT mice ( P < 0.05), which was reversed ( P < 0.05) by either N-acetyl-l-cysteine, apocynin, gp91ds-tat, or indomethacin, suggesting the contribution of reactiv...

Canadian Journal of Cardiology, 2015

Background: Circulating levels of angiopoietin-like 2 (ANGPTL2), a proinflammatory and proatherog... more Background: Circulating levels of angiopoietin-like 2 (ANGPTL2), a proinflammatory and proatherogenic protein, are elevated in patients with coronary artery disease (CAD). We hypothesized that highintensity intermittent exercise (HIIE), known to be beneficial in patients with CAD, would reduce circulating ANGPTL2 levels. Methods: Plasma levels of ANGPTL2 were measured before and 20 minutes, 24 hours, and 72 hours after an acute exercise session in a crossover study comparing HIIE to moderate-intensity continuous exercise (MICE) in 14 patients with CAD and 20 age-matched and 20 young healthy controls. Results: Pre-exercise ANGPTL2 levels were 3-fold higher in patients with CAD than in age-matched controls (P < 0.05) and correlated negatively with VO 2max /lean body mass (P < 0.0001

Pflügers Archiv - European Journal of Physiology, 2013

We aimed to evaluate the lasting functional imprinting of exercise (EX) and catechin (CAT) on the... more We aimed to evaluate the lasting functional imprinting of exercise (EX) and catechin (CAT) on the vascular function of middle-age mice switched to a proatherogenic environment. C57BL/6J mice (n=10-15 in each group) fed a regular diet (RD) were exposed from the age of 1 to 9 months either to EX (voluntary running; 2.7± 0.2 km/day), to the polyphenol CAT (30 mg/kg/day in drinking water), or to physical inactivity (PI). At 9 months of age, EX and CAT were stopped and mice either remained on the RD or were fed a Western diet (WD) for an additional 3 months. At 12 months of age, mice from all groups fed a WD had similar body mass, systolic blood pressure, and plasma total cholesterol, glucose, insulin, and isoprostane. Compared to the RD, the WD induced an indomethacin-sensitive aortic endothelium-dependent and independent dysfunction in PI mice (p<0.05) that was prevented by both EX and CAT; this benefit was associated with a higher (p< 0.05) non-nitric oxide/non-prostacyclin endothelium-dependent relaxation. While EX, but not PI or CAT, prevented vascular dysfunction induced by the WD in cerebral arteries, it had no effect in femoral arteries. The profiles of activity of antioxidant enzymes and of proinflammatory gene expression in the aorta suggest a better adaptation of EX>CAT>PI mice to stress. In conclusion, our data suggest that a postnatal exposure to EX, but not to CAT, imprints an adaptive defense capacity in the vasculature against a deleterious change in lifestyle.

Mechanisms of Ageing and Development, 2010

ABSTRACT

AJP: Regulatory, Integrative and Comparative Physiology, 2010

Endogenous endothelin-1-dependent (ET-1) tone in coronary arteries depends on the balance between... more Endogenous endothelin-1-dependent (ET-1) tone in coronary arteries depends on the balance between ETA and ETB receptor-mediated effects and on parameters such as receptor distribution and endothelial integrity. Numerous studies highlight the striking functional interactions that exist between nitric oxide (NO) and ET-1 in the regulation of vascular tone. Many of the cardiovascular complications associated with cardiovascular risk factors and aging are initially attributable, at least in part, to endothelial dysfunction characterized by a dysregulation between NO and ET-1. The contribution of the imbalance between smooth muscle ETA/B and endothelial ETB receptors to this process is poorly understood. An increased contribution of ET-1 that is associated with a proportional decrease in that of NO accompanies the development of coronary endothelial dysfunction, coronary vasospasm, and atherosclerosis. These data form the basis for the rationale of testing therapeutic approaches countera...

Circulation, 2014

Introduction: Exercise training in patients who have suffered an acute coronary syndrome is assoc... more Introduction: Exercise training in patients who have suffered an acute coronary syndrome is associated with a significant reduction in mortality and cardiovascular events. Moderate intensity continuous exercise training (MICET) is currently recommended. Recently, high-intensity interval training (HIIT), that utilizes short bursts of very intense efforts interspersed with periods of recovery, has been explored as an alternative to MICET. The safety aspects of HIIT in patients post acute coronary syndrome (ACS) have been poorly described. Methods: Thirty-seven low-risk patients post ACS (65% STEMI, fully revascularized, EF > 40%, age 61±9 years, 8 women) were randomized 4 weeks to 6 months post ACS; to 12 to 18 weeks of 2-3 sessions/week (total: 36 sessions) of isocaloric MICET or HIIT on cycle ergometer. VO2peak and maximal aerobic power (MAP) were determined using maximal cardiopulmonary exercise test (CPET) on cycle ergometer and continuous ECG and BP were monitored every 2 min....

International Journal of Molecular Sciences, 2021

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible... more Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in whic...

Aging, 2019

Elimination of senescent cells (SnC) is anti-atherogenic, but the specific contribution of senesc... more Elimination of senescent cells (SnC) is anti-atherogenic, but the specific contribution of senescent vascular endothelial cells (EC) is unknown. We inactivated angiopoietin like-2 (angptl2), a marker of SnEC and a proatherogenic cytokine in LDLr-/-, hApoB100 +/+ atherosclerotic (ATX) mice. Three months after a single vascular delivery of a small hairpin (sh)Angptl2 in 3-month old ATX mice using an adeno-associated virus serotype 1 (AAV1), aortic atheroma plaque progression was slowed by 58% (p<0.0001). In the native aortic endothelium, angptl2 expression was decreased by 80%, in association with a reduced expression of p21, a cyclin-dependent kinase inhibitor overexpressed in growth-arrested SnC. Endothelial activation was reduced (lower Icam-1, Il-1β and Mcp-1 expression), decreasing monocyte Cd68 expression in the endothelium. One week post-injection, the ratio Bax/Bcl2 increased in the endothelium only, suggesting that angptl2 + /p21 + SnEC were eliminated by apoptosis. Four weeks post-injection, the endothelial progenitor marker Cd34 increased, suggesting endothelial repair. In arteries of atherosclerotic patients, we observed a strong correlation between p21 and ANGPTL2 (r=0.727, p=0.0002) confirming the clinical significance of angptl2-associated senescence. Our data suggest that therapeutic down-regulation of vascular angptl2 leads to the clearance of SnEC by apoptosis, stimulates endothelial repair and reduces atherosclerosis.

American Journal of Physiology-Heart and Circulatory Physiology, 2018

Aging is a modern concept: human life expectancy has more than doubled in less than 150 yr in Wes... more Aging is a modern concept: human life expectancy has more than doubled in less than 150 yr in Western countries. Longer life span, however, reveals age-related diseases, including cerebrovascular diseases. The vascular system is a prime target of aging: the “wear and tear” of large elastic arteries exposed to a lifelong pulsatile pressure causes arterial stiffening by fragmentation of elastin fibers and replacement by stiffer collagen. This arterial stiffening increases in return the amplitude of the pulse pressure (PP), its wave penetrating deeper into the microcirculation of low-resistance, high-flow organs such as the brain. Several studies have associated peripheral arterial stiffness responsible for the sustained increase in PP, with brain microvascular diseases such as cerebral small vessel disease, cortical gray matter thinning, white matter atrophy, and cognitive dysfunction in older individuals and prematurely in hypertensive and diabetic patients. The rarefaction of white ...

Circulation, Jan 19, 2018

American journal of hypertension, 2017

Angiopoietin-like-2 (ANGPTL2) is a secreted proinflammatory glycoprotein that promotes endothelia... more Angiopoietin-like-2 (ANGPTL2) is a secreted proinflammatory glycoprotein that promotes endothelial dysfunction, atherosclerosis, and cardiovascular disease (CVD). Circulating ANGPTL2 is increased in chronic kidney disease (CKD), where the risk of CVD is amplified. The objectives of the present study were to (i) examine whether kidney transplantation (KTx) reduces ANGPTL2 levels, (ii) identify the determinants of ANGPTL2 after KTx, (iii) study the association of ANGPTL2 with aortic stiffness, and (iv) assess the impact of ANGPTL2 on mortality after KTx. In 75 patients, serum ANGPTL2 levels were measured at baseline and 3 months after KTx. Aortic stiffness was determined by carotid-femoral pulse wave velocity, glomerular filtration rate was estimated by CKD-EPI formula, and serum cytokines and endothlin-1 levels were determined 3 months after KTx. Survival analysis was performed using Kaplan-Meier and Cox regression after a median follow-up of 90 months. After 3 months of KTx, ANGPTL2...

PloS one, 2016

Pro-inflammatory angiopoietin-like 2 (angptl2) promotes endothelial dysfunction in mice and circu... more Pro-inflammatory angiopoietin-like 2 (angptl2) promotes endothelial dysfunction in mice and circulating angptl2 is higher in patients with cardiovascular diseases. We previously reported that a single bout of physical exercise was able to reduce angptl2 levels in coronary patients. We hypothesized that chronic exercise would reduce angptl2 in patients with post-acute coronary syndrome (ACS) and endothelial dysfunction. Post-ACS patients (n = 40, 10 women) were enrolled in a 3-month exercise-based prevention program. Plasma angptl2, hs-CRP, and endothelial function assessed by scintigraphic forearm blood flow, were measured before and at the end of the study. Exercise increased VO2peak by 10% (p<0.05), but did not significantly affect endothelial function, in both men and women. In contrast, exercise reduced angptl2 levels only in men (-26±7%, p<0.05), but unexpectedly not in women (+30±16%), despite similar initial levels in both groups. Exercise reduced hs-CRP levels in men b...

Diabetologia, 2016

Aims/hypothesis A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk f... more Aims/hypothesis A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk factor for developing diabetes and is associated with insulin resistance and atherosclerosis. In this work, we have examined the impact of serum ANGPTL2 on improving cardiovascular (CV) risk stratification in patients with type 2 diabetes. Methods A prospective, monocentric cohort of consecutive type 2 diabetes patients (the SURDIAGENE cohort; total of 1353 type 2 diabetes patients; 58% men, mean ± SD age 64 ± 11 years) was followed for a median of 6.0 years for death as primary endpoint and major adverse CV events (MACE; i.e. CV death, myocardial infarction or stroke) as a secondary endpoint. Patients with end-stage renal disease, defined as a requirement for dialysis or a history of kidney transplantation, Eric Thorin and Samy Hadjadj contributed equally to this study.

American journal of physiology. Heart and circulatory physiology, Jan 5, 2016

While heart rate reduction (HRR) is a target for the management of patients with heart disease; c... more While heart rate reduction (HRR) is a target for the management of patients with heart disease; contradictory results were reported using ivabradine, which selectively inhibits the pacemaker If current, vs. β-blockers like metoprolol. This study aimed at testing whether similar HRR with ivabradine vs. metoprolol differentially modulates cardiac energy substrate metabolism, a factor determinant for cardiac function, in a mouse model of dyslipidemia (hApoB(+/+);LDLR(-/-)). Following a longitudinal study design, we used 3- and 6-month-old mice, untreated or treated for 3 months with ivabradine or metoprolol. Cardiac function was evaluated in vivo, and ex vivo in working hearts perfused with (13)C-labeled substrates to assess substrate fluxes through energy metabolic pathways. Compared to 3-month-old, 6-month-old dyslipidemic mice had similar cardiac hemodynamics in vivo, but impaired (P<0.001) contractile function (aortic flow:-45%; cardiac output:-34%; stroke volume:-35%) and glyco...

PloS one, 2016

Exercise is an effective approach for primary and secondary prevention of cardiovascular diseases... more Exercise is an effective approach for primary and secondary prevention of cardiovascular diseases (CVD) and loss of muscular mass and function. Its benefits are widely documented but incompletely characterized. It has been reported that exercise can induce changes in the expression of antioxidant enzymes including Sod2, Trx1, Prdx3 and Gpx1 and limits the rise in oxidative stress commonly associated with CVD. These enzymes can be subjected to epigenetic regulation, such as DNA methylation, in response to environmental cues. The aim of our study was to determine whether in the early stages of atherogenesis, in young severely dyslipidemic mice lacking LDL receptors and overexpressing human ApoB100 (LDLR-/-; hApoB+/+), exercise regulates differentially the expression of antioxidant enzymes by DNA methylation in the skeletal muscles that consume high levels of oxygen and thus generate high levels of reactive oxygen species. Expression of Sod2, Txr1, Prdx3 and Gpx1 was altered by 3 month...

PloS one, 2016

DNA methylation is believed to regulate gene expression during adulthood in response to the const... more DNA methylation is believed to regulate gene expression during adulthood in response to the constant changes in environment. The methylome is therefore proposed to be a biomarker of health through age. ANGPTL2 is a circulating pro-inflammatory protein that increases with age and prematurely in patients with coronary artery diseases; integrating the methylation pattern of the promoter may help differentiate age- vs. disease-related change in its expression. We believe that in a pro-inflammatory environment, ANGPTL2 is differentially methylated, regulating ANGPTL2 expression. To test this hypothesis we investigated the changes in promoter methylation of ANGPTL2 gene in leukocytes from patients suffering from post-acute coronary syndrome (ACS). DNA was extracted from circulating leukocytes of post-ACS patients with cardiovascular risk factors and from healthy young and age-matched controls. Methylation sites (CpGs) found in the ANGPTL2 gene were targeted for specific DNA methylation qu...

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, Jan 28, 2016

Arterial blood pressure is oscillatory; whether pulse pressure (PP) regulates cerebral artery myo... more Arterial blood pressure is oscillatory; whether pulse pressure (PP) regulates cerebral artery myogenic tone (MT) and endothelial function is currently unknown. To test the impact of PP on MT and dilation to flow (FMD) or to acetylcholine (Ach), isolated pressurized mouse posterior cerebral arteries were subjected to either static pressure (SP) or a physiological PP (amplitude: 30 mm Hg; frequency: 550 bpm). Under PP, MT was significantly higher than in SP conditions (p < 0.05) and was not affected by eNOS inhibition. In contrast, under SP, eNOS inhibition increased (p < 0.05) MT to levels observed under PP, suggesting that PP may inhibit eNOS. At a shear stress of 20 dyn/cm(2), FMD was lower (p < 0.05) under SP than PP. Under SP, eNOS-dependent [Formula: see text] production contributed to FMD, while under PP, eNOS-dependent NO was responsible for FMD, indicating that PP favours eNOS coupling. Differences in FMD between pressure conditions were abolished after NOX2 inhibiti...

Applied Physiology, Nutrition, and Metabolism, 2016

Cardiovascular risk factors are known to exacerbate high-saturated fatty acid meal (HSFAM)-induce... more Cardiovascular risk factors are known to exacerbate high-saturated fatty acid meal (HSFAM)-induced endothelial dysfunction, but the influence of subclinical metabolic dysregulations and the acute impact of a single mixed Mediterranean-type meal (MMM) remains unknown. Thus, this study has the objective to evaluate the metabolic and vascular effect of such meals in healthy subjects with or without subclinical fasting metabolic dysregulations. Twenty-eight healthy males without overt cardiovascular risk factors randomly ingested 1 of 2 isocaloric meals on separate days. Plasma metabolic markers, fatty acid (FA) profile, and endothelial function (flow-mediated dilatation; FMD) were assessed at baseline and 2 and 4 h after meal ingestion. Unsupervised hierarchical clustering identified 2 subgroups of participants (n = 11 and 17) differing by their baseline metabolic profiles. The MMM did not significantly alter postprandial endothelial function in all subjects, irrespective of baseline m...

Circulation, Nov 25, 2014

Introduction: Angiopoietin-like 2 (angptl2) is a circulating pro-inflammatory and pro-oxidative p... more Introduction: Angiopoietin-like 2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein that induces endothelial dysfunction in mice. Plasma angptl2 levels are increased in diabetic or atherosclerotic patients, while a lifestyle intervention has been shown to decrease angptl2 expression in overweight, but otherwise healthy men. Whether angptl2 levels are sensitive to exercise in CAD patients is unknown. Hypothesis: Exercise training reduces angptl2 levels in patients with CAD and endothelial dysfunction. Methods: Stable and optimally treated CAD patients (n=31, 60±2 y/o, 7 females) were enrolled in a 3-month exercise-based prevention program at the Montreal Heart Institute. Blood samples were collected before and at the end of the study to measure plasma levels of angptl2 (ELISA) and of hs-CRP. Endothelial function was assessed by measuring the ratio of the slope of the nuclear tracer Myoview activity-time in the right to the left arm. A ratio lower than 3.55 is indicative of endothelial dysfunction. Data are mean±SEM. Results: Exercise training was associated with a 11% increase in maximal cardiopulmonary capacity (VO2max; p=0.003). Endothelial function was not affected by exercise (from 3.41±0.25 to 3.58±0.26; p=0.455), but plasma levels of angptl2 were significantly decreased by 32% (from 3.4±0.7 to 2.3±0.4 ng/ml; p=0.020), while hs-CRP levels were unaffected (from 2.2±0.5 to 1.5±0.2 mg/l; p=0.155). Levels of angptl2 (but not of hs-CRP) were negatively correlated with VO2max (p=0.0471, r=0.257): the lower angptl2, the fitter the patient. In addition, levels of angptl2 (but not of hs-CRP) were negatively correlated with endothelial function (p=0.0217, r=0.304): the lower angptl2, the better the endothelial function. Importantly, exercise training was associated with a reduction in angptl2 levels (from 4.3±1.2 to 2.5±0.6 ng/ml; p=0.011, n=18) only among individuals with endothelial dysfunction at baseline, but not in patients with normal endothelial function (from 2.2±0.4 to 1.7±0.4 ng/ml; p=0.350, n=11). Conclusions: In CAD patients with endothelial dysfunction, angptl2 levels are sensitive to exercise training. Low levels of angptl2 may reflect good cardiopulmonary fitness and endothelial function.

Journal of the American Heart Association, Jan 10, 2013

Angiopoietin like-2 (angptl2), a proinflammatory protein, is overexpressed in endothelial cells (... more Angiopoietin like-2 (angptl2), a proinflammatory protein, is overexpressed in endothelial cells (ECs) from patients with coronary artery disease (CAD). Whether angptl2 contributes to atherogenesis is unknown. We tested the hypothesis that angptl2 promotes inflammation and leukocyte adhesion onto ECs, thereby accelerating atherogenesis in preatherosclerotic dyslipidemic mice. In ECs freshly isolated from the aorta, basal expression of TNF-α and IL-6 mRNA was higher in 3-month-old severely dyslipidemic mice (LDLr(-/-); hApoB100(+/+) [ATX]) than in control healthy wild-type (WT) mice (P<0.05) and was increased in both groups by exogenous angptl2 (100 nmol/L). Angptl2 stimulated the adhesion of leukocytes ex vivo on the native aortic endothelium of ATX, but not WT mice, in association with higher expression of ICAM-1 and P-selectin in ECs (P<0.05). Antibodies against these endothelial adhesion molecules prevented leukocyte adhesion. Intravenous administration of angptl2 for 1 mont...

AJP: Heart and Circulatory Physiology, 2015

Angiopoietin like-2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein, but it... more Angiopoietin like-2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein, but its role in regulating cerebral endothelial function remains unknown. We hypothesized that in mice knockdown (KD) of angptl2, cerebral endothelial function would be protected against ANG II-induced damage. Subcutaneous infusion of ANG II (200 ng·kg−1·min−1, n = 15) or saline ( n = 15) was performed in 20-wk-old angptl2 KD mice and wild-type (WT) littermates for 14 days. In saline-treated KD and WT mice, the amplitude and the sensitivity of ACh-induced dilations of isolated cerebral arteries were similar. However, while endothelial nitric oxide (NO) synthase (eNOS)-derived O2−/H2O2 contributed to dilation in WT mice, eNOS-derived NO ( P < 0.05) was involved in KD mice. ANG II induced cerebral endothelial dysfunction only in WT mice ( P < 0.05), which was reversed ( P < 0.05) by either N-acetyl-l-cysteine, apocynin, gp91ds-tat, or indomethacin, suggesting the contribution of reactiv...

Canadian Journal of Cardiology, 2015

Background: Circulating levels of angiopoietin-like 2 (ANGPTL2), a proinflammatory and proatherog... more Background: Circulating levels of angiopoietin-like 2 (ANGPTL2), a proinflammatory and proatherogenic protein, are elevated in patients with coronary artery disease (CAD). We hypothesized that highintensity intermittent exercise (HIIE), known to be beneficial in patients with CAD, would reduce circulating ANGPTL2 levels. Methods: Plasma levels of ANGPTL2 were measured before and 20 minutes, 24 hours, and 72 hours after an acute exercise session in a crossover study comparing HIIE to moderate-intensity continuous exercise (MICE) in 14 patients with CAD and 20 age-matched and 20 young healthy controls. Results: Pre-exercise ANGPTL2 levels were 3-fold higher in patients with CAD than in age-matched controls (P < 0.05) and correlated negatively with VO 2max /lean body mass (P < 0.0001

Pflügers Archiv - European Journal of Physiology, 2013

We aimed to evaluate the lasting functional imprinting of exercise (EX) and catechin (CAT) on the... more We aimed to evaluate the lasting functional imprinting of exercise (EX) and catechin (CAT) on the vascular function of middle-age mice switched to a proatherogenic environment. C57BL/6J mice (n=10-15 in each group) fed a regular diet (RD) were exposed from the age of 1 to 9 months either to EX (voluntary running; 2.7± 0.2 km/day), to the polyphenol CAT (30 mg/kg/day in drinking water), or to physical inactivity (PI). At 9 months of age, EX and CAT were stopped and mice either remained on the RD or were fed a Western diet (WD) for an additional 3 months. At 12 months of age, mice from all groups fed a WD had similar body mass, systolic blood pressure, and plasma total cholesterol, glucose, insulin, and isoprostane. Compared to the RD, the WD induced an indomethacin-sensitive aortic endothelium-dependent and independent dysfunction in PI mice (p<0.05) that was prevented by both EX and CAT; this benefit was associated with a higher (p< 0.05) non-nitric oxide/non-prostacyclin endothelium-dependent relaxation. While EX, but not PI or CAT, prevented vascular dysfunction induced by the WD in cerebral arteries, it had no effect in femoral arteries. The profiles of activity of antioxidant enzymes and of proinflammatory gene expression in the aorta suggest a better adaptation of EX>CAT>PI mice to stress. In conclusion, our data suggest that a postnatal exposure to EX, but not to CAT, imprints an adaptive defense capacity in the vasculature against a deleterious change in lifestyle.

Mechanisms of Ageing and Development, 2010

ABSTRACT

AJP: Regulatory, Integrative and Comparative Physiology, 2010

Endogenous endothelin-1-dependent (ET-1) tone in coronary arteries depends on the balance between... more Endogenous endothelin-1-dependent (ET-1) tone in coronary arteries depends on the balance between ETA and ETB receptor-mediated effects and on parameters such as receptor distribution and endothelial integrity. Numerous studies highlight the striking functional interactions that exist between nitric oxide (NO) and ET-1 in the regulation of vascular tone. Many of the cardiovascular complications associated with cardiovascular risk factors and aging are initially attributable, at least in part, to endothelial dysfunction characterized by a dysregulation between NO and ET-1. The contribution of the imbalance between smooth muscle ETA/B and endothelial ETB receptors to this process is poorly understood. An increased contribution of ET-1 that is associated with a proportional decrease in that of NO accompanies the development of coronary endothelial dysfunction, coronary vasospasm, and atherosclerosis. These data form the basis for the rationale of testing therapeutic approaches countera...