Julie Lalongé

Lower Methylation of the ANGPTL2 Gene in Leukocytes from Post-Acute Coronary Syndrome Patients.

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 quantification. The functionality of ANGPTL2 methylation was assessed by an in vitro luciferase assay. In post-ACS patients, C-reactive protein and ANGPTL2 circulating levels increased significantly when compared to healthy controls. Decreased methylation of specific CpGs were found in the promoter of ANGPTL2 and allowed to discriminate age vs. disease associated methylation. In vitro DNA methylation of specific CpG lead to inhibition of ANGPTL2 promoter activity. Reduced leukocyte DNA methylation in the promoter region of ANGPTL2 is associated with the pro-inflammatory environment that characterizes patients with post-ACS differently from age-matched healthy controls. Methylation of different CpGs in ANGPTL2 gene may prove to be a reliable biomarker of coronary disease.

Exercise Lowers Plasma Angiopoietin-Like 2 in Men with Post-Acute Coronary Syndrome

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 but not in women. In men, levels of angptl2, but not of hs-CRP, reached at the end of the training program were negatively correlated with VO2peak (r = -0.462, p = 0.012) and with endothelial function (r = -0.419, p = 0.033) measured at baseline: better initial cardiopulmonary fitness and endothelial function correlated with lower angptl2 levels after exercise. Pre-exercise angptl2 levels were lower if left ventricular ejection time was long (p<0.05) and the drop in angptl2 induced by exercise was greater if the cardiac output was high (p<0.05). In conclusion, in post-ACS men, angptl2 levels are sensitive to chronic exercise training. Low circulating angptl2 reached after training may reflect good endothelial and cardiopulmonary functions.

STATIN THERAPY DECREASES VO2PEAK WITHOUT AFFECTING EXERCISE ENDURANCE, ENDOTHELIAL FUNCTION OR ARTERIAL STIFFNESS AMONG SUBJECTS WITH PRIMARY UNTREATED HYPERCHOLESTEROLEMIA

(CO) and cerebral oxygenation/perfusion (COP) in heart transplant recipients (HTR) and age-matched controls (AMC) during maximal exercise (ME), 2) to study the relationships between VO2 peak, CO, COP inHTR and AMC. 27 AMC and 26HTR were recruited. VO2 peak and cardiac hemodynamic (impedance cardiography) were measured during a ME. COP (O2Hb, tHb) was measured using near-infrared spectroscopy (NIRS). RESULTS: Compared to AMC, HTR had a lower VO2 peak (ml/min/kg of lean body mass), maximal (max) cardiac index (CImax), max ventilation, max tidal volume and max respiratory frequency vs. AMC (P<0,0001). End-systolic volume index and systemic vascular resistance index were higher inHTR (P<0,05). At 50% and 75% of peak, O2Hb was lower in HTR (P<0,05). At 100% of peak, tHbwas lower inHTR (P<0,05). At recovery, O2Hb and tHb were lower in HTR (P<0,05). VO2 peak (ml/ min/kg) and CImax were correlated to DO2Hb (R1⁄40,33 and 0,36, P<0,05) and DtHb (R1⁄40,35 and 0,44, P<0,01). CONCLUSION: VO2 peak is reduced in HTR because of central, ventilator, peripheral factors and medication. Lower VO2 peak and CImax in HTR does not seem to really affect COP during exercise. During exercise, our results suggest a lower O2 saturation in HTR. In HTR, the lower tHb at ME could be due to a better physical capacity in AMC. In HTR, differences in COP during recovery could be explained by the absence of cardiac overshoot phenomenon, medication and/or endothelial dysfunction.