endothelin-1 and Hyperlipoproteinemia-Type-II

Lipid-apheresis (LA) is thought to improve microcirculation. However, limited data are available on the effects on peripheral microcirculation. We investigated upper limb microcirculation of 22 patients undergoing regular LA on a weekly basis before and after LA. Using standardized semiquantitative scales, we analyzed blood flow, vasomotor function, and erythrocyte aggregation by capillary microscopy. In addition, capillary blood flow in quiescence and under heat and cryo-stress was evaluated by photoplethysmographic and laser Doppler anemometry. Moreover, levels of vasoactive mediators adrenalin, noradrenalin, endothelin-1 (ET-1), atrial natriuretic peptide (ANP), asymmetrical dimethyl-arginine (ADMA), as well as total protein and fibrinogen were measured. We found a significant increase in blood flow, the number of perfused capillaries and an improvement of erythrocyte aggregation by capillary microscopy. Using laser Doppler anemometry, we were able to show that this increase was predominantly located in the superficial layer capillaries (Δ44.53 ± 135.81%, n.s.) and less so in deeper layer arterioles (Δ2.75 ± 24.84%, n.s.). Vascular response to heat and cryo stress was also improved after LA but failed to reach significance. LA significantly reduced levels of epinephrin (-33 ± 39.2%), ANP (-28.8 ± 20.2%), ADMA (-74.1 ± 23%), and fibrinogen (-45.4 ± 19.7%) when comparing before LA and after LA values. In summary, we found an improvement in the microcirculation of the upper limbs under LA, which may result from a decrease of vasoconstrictors, improvement of vasomotor function, and a decrease in blood viscosity or erythrocyte aggregation.

Topics: Adult; Aged; Arginine; Atrial Natriuretic Factor; Blood Component Removal; Blood Flow Velocity; Endothelin-1; Epinephrine; Erythrocyte Aggregation; Female; Fibrinogen; Hand; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Laser-Doppler Flowmetry; Lipids; Male; Microcirculation; Microscopic Angioscopy; Middle Aged; Norepinephrine; Photoplethysmography

Our lab has shown that left circumflex coronary artery (LCX) perivascular adipose tissue (PAT) blunts endothelin-1 (ET-1)-induced maximal contractions in normal pigs on low- and high-fat diets. Other studies report that PAT exerts anticontractile effects on agonist-induced arterial contraction via release of a relaxing factor that acts on the underlying vasculature. The purpose of this study was to test the hypotheses that PAT blunts LCX contraction in familial hypercholesterolemic pigs and that exercise training (Ex) augments this anticontractile effect. Male familial hypercholesterolemic pigs were divided into Ex (n = 13) and sedentary (Sed) (n = 15) groups. LCX reactivity to angiotensin II (ANG II), bradykinin (BK), ET-1, and sodium nitroprusside (SNP) was evaluated in vitro with intact or removed PAT in Sed and Ex familial hypercholesterolemic pigs. LCX relaxation induced by BK and SNP was not altered by Ex or PAT removal. LCX contractions stimulated by ANG II and ET-1 were not significantly altered by Ex or PAT removal across doses; however, Ex did act to significantly reduce ET-1 maximal contractions in familial hypercholesterolemic pig LCX compared with Sed familial hypercholesterolemic pig LCX, independent of PAT (P < 0.05). We conclude that LCX PAT in Sed and Ex familial hypercholesterolemic pigs exerts no substantial anticontractile influence over LCX vasomotor responses to endogenous constrictors such as ANG II and ET-1. Our results suggest that exercise training significantly reduces familial hypercholesterolemic pig LCX maximal contractile responses to the endogenous constrictor ET-1, independent of PAT.

Topics: Adipose Tissue; Angiotensin II; Animals; Atherosclerosis; Bradykinin; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Hyperlipoproteinemia Type II; Male; Nitroprusside; Physical Exertion; Sedentary Behavior; Swine; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Patients with the heterozygous form of familial hypercholesterolemia (FH) display an early onset of atherosclerosis due to disturbed vascular-endothelial function. Whether the improvements of endothelial function after lipid apheresis are mediated by increased NO-production or by an altered turnover of vasoconstrictors such as ET-1 is still unknown. This was the onset of the present study.. Patients with FH and advanced atherosclerosis receiving regular LDL apheresis at 1 to 3 weeks were recruited. Lipids, L-arginine (L-Arg), L-hydroxyarginine (NHA), L-citrulline as well as big endothelin (Big-ET) and endothelin (ET-1) were measured after DALI, HELP and TheraSorb apheresis.. 17 patients with severe FH aged 55.6 years (mean) received a total of 30 treatments. TC, LDL-C, HDL-C, TG and TC / HDL-C ratio were reduced (55, 70, 9, 48, and 52%; p<0.01) with no differences between apheresis systems. L-Arg was reduced after apheresis (HELP -18.0%, DALI -26.5%; Therasorb -7.6%) and returned to baseline after 2 h. Big-ET (p<0.01) and ET-1 were found to be increased directly and 2 hours after apheresis with HELP while transiently decreasing with DALI and Therasorb.. Improvement of endothelial function after apheresis seems to have multifaceted causes. The further elucidation of the interrelationship between endothelial dysfunction and restricted NO synthesis, as addressed in this study by measuring L-NHA, L-Arg, L-Cit, ET-1 and Big-ET will be necessary in the future.

Topics: Adult; Aged; Analysis of Variance; Arginine; Atherosclerosis; Biomarkers; Blood Component Removal; Case-Control Studies; Citrulline; Endothelin-1; Female; Humans; Hyperlipoproteinemia Type II; Lipids; Male; Middle Aged; Nitric Oxide; Pilot Projects; Treatment Outcome

Familial hypercholesterolemia (FH) is characterized by a high incidence of coronary heart disease. Evidence suggests an important role for angiotensin II (AngII) in the fibrotic response to tissue injury, and in promoting myocardial hypertrophy via paracrine mechanisms mediated by fibroblasts. We sought to determine whether AngII promotes proliferative and pro-atherogenic responses in FH patients.. We used primary fibroblasts -- from five patients with heterozygous FH and five control subjects (C) -- to study AngII-induced cell growth, intracellular calcium fluxes, and expression/release of matrix components and pro-inflammatory peptides [transforming growth factor-beta1 (TGFbeta1) and endothelin-1 (ET-1)] and metalloproteinases involved in plaque remodeling and vulnerability.. AngII stimulated cell replication (5.1 +/- 0.03 versus 3.2 +/- 0.04 cells/50 cells per well, P < 0.001), and induced a larger increase in intracellular calcium content in FH cells than in C cells, in a dose-dependent fashion (mean difference = 76 nmol/l, P < 0.001). Similarly, TGFbeta1 and ET-1 expression and release were potentiated (after 24-h incubation with 1 micromol/l AngII: TGFbeta1 was 190 +/- 12 in C and 376 +/- 9 pg/ml per 10(6) cells in FH, and ET-1 was 93 +/- 5 in C and 192 +/- 7 pmol/ml per 10(6) cells in FH; P < 0.001 for both). AngII-induced release of the metalloproteinases MMP-1 and MMP-2 was also increased in FH versus C cells (0.52 +/- 0.04 versus 0.36 +/- 0.05 and 24 +/- 4 versus 13 +/- 3 ng/mg protein with 1 micromol/l AngII). These enhanced responses were likely due to an increased angiotensin receptor 1 (AT1) expression in cells from FH patients induced by AngII, and were prevented by pretreating cells with the selective AT1 antagonist irbesartan.. These findings show that some AngII-mediated pathways are enhanced in FH subjects irrespective of the presence of low-density lipoprotein (LDL), thus contributing to the development and progression of atherosclerosis in these patients.

Topics: Adult; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Arteriosclerosis; Biphenyl Compounds; Calcium; Case-Control Studies; Cell Proliferation; Cells, Cultured; Cholesterol, LDL; Dose-Response Relationship, Drug; Endothelin-1; Female; Fibroblasts; Heterozygote; Humans; Hyperlipoproteinemia Type II; Irbesartan; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Middle Aged; Receptor, Angiotensin, Type 1; Tetrazoles; Transforming Growth Factor beta