Abstract 31: High-density Lipoprotein, a Feed-forward Forechecking Loop

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
A.-l. Behnke ◽  
F. Mockenhaupt ◽  
K. Willy ◽  
K. Winkler ◽  
R. Hetzer ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Density Lipoprotein ◽  
Vascular Wall ◽  
Isometric Tension ◽  
Diffusion Control ◽  
Affinity Constant ◽  
Feed Forward ◽  
Heart Transplantations ◽  
Receptor Sites ◽  
Relative Contraction

Background: The protective effect of HDL is projected into the cholesterol back-transport of breakdown products of lipid metabolism to the liver. This is a feed-back circuit which controls cholesterol exit. Cholesterol entry could be safeguarded in a feed-forward forechecking loop at the proteoglycan (PG) receptor sites (syndecan, perlecan). HDL is the counter partner in the system of internalization and diffusion control for lipoprotein entry into the vascular wall. Based on stereochemical and chiral conformity with its PG receptor and the much higher negative charge density, HDL owns by far a higher affinity compared with LDL. Methods: Flow-dependent isometric tension, intracellularly recorded membrane potential and cAMP-cGMP were measured in segments of 25 coronaries from heart transplantations. Results and Discussion: Compared to Krebs solution, LDL (100 mg/dL) impaired flow-dilatation and caused a relative contraction by 18.5% (Table). In contrast, HDL (50 mg/dL) and HDL+LDL stimulated flow-dilatation by 31.1% and 41.4%, respectively (p < 0.96). Thus, the contractile effect of LDL was absent in the Krebs-HDL-LDL solution. The same effects were apparent in the membrane potential and cAMP-cGMP-concentrations of the VSM cells. These results are confirmed by ellipsometry measurements, where nanoplaque formation by LDL is suppressed by preincubation with HDL [Siegel, Malmsten, Ermilov: Adv Coll Interface Sci 205 (2014) 275-318]. Conclusion: LDL-cholesterol entry into the vascular wall is effectfully controlled by HDL in a feed-forward forechecking loop (HDL 4х higher affinity constant to the PG receptor). The interaction between both is dominated by competition.

Abstract 166: Interaction Between LDL and Sympathetic Adrenoreceptors

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Daniel Grün ◽  
Janna Lendner ◽  
Stephan Krohn ◽  
Agnes Jumar ◽  
Andreas Zakrzewicz ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Isometric Tension ◽  
Heart Transplantations ◽  
Lower Blood ◽  
Measured Effect ◽  
Relative Contraction ◽  
Pressure Independent ◽  
Stimulation Of

Introduction: LDL is a significant risk factor for cardiovascular disease and is known to impair flow-dependent vasodilatation. Furthermore, it has been demonstrated that LDL can even directly cause vasoconstricton. Recent studies suggested that lower LDL levels, achieved through administration of statins, are correlated with lower blood pressure, independent from pleiotropic statin effects. Our objective was to investigate whether LDL-induced impairment in flow-dilatation was due to an interaction of LDL with sympathetic adrenoreceptors. Materials and Methods: Flow-dependent isometric tension, intracellularly recorded membrane potential and cAMP-cGMP were measured in segments of 22 coronaries from heart transplantations. Results: As compared to Krebs solution, LDL affected flow-dilatation and caused a relative contraction [Δ(T 3 -T 100 ): Krebs 0.459 g; LDL 0.278 g]. Complete blockade of both α- (phentolamine 10 -7 mol/L) and β-receptors (propranolol 10 -7 mol/L) resulted in a ∼50% reduction of flow-dilatation impairment induced by LDL. Blockage of either α- (1) or β-receptors (2) showed smaller effects which added up to the measured effect under blockade of both receptors (4). Similar effects were apparent in the recorded membrane potential of the vascular smooth muscle cells. Discussion: We conclude that the LDL-induced impairment in flow-dependent dilatation is partially due to the interaction between lipoprotein and both α- and β-adrenoreceptors. Since blockade of each receptor resulted in a relative dilatation, we assume that the LDL effect is caused by a stimulation of α-adrenoreceptors and an inhibition of β-adrenoreceptors.

Mobilization of Fibrinogen Receptor Sites on Human Platelets Stimulated with ADP is Prevented by Prostacyclin

1979 ◽  
Author(s):  
J. Hawiger ◽  
S. Parkinson ◽  
S. Timmons
Keyword(s):  
Inhibitory Effect ◽  
Human Platelets ◽  
Affinity Constant ◽  
Human Fibrinogen ◽  
Fibrinogen Receptor ◽  
Receptor Sites ◽  
Plasma Factor ◽  
Potent Inhibitory Effect

Fibrinogen is a plasma factor required for aggregation of human platelets by ADP. The mechanism of platelet-ADP-fibrinogen interaction was studied by measuring the equilibrium binding of 125I-fibrinogen to human platelets separated from plasma proteins. Binding of 125I-fibrinogen to platelets not stimulated with ADP was low and unaffected by an excess of unlabel led fibrinogen. However, when platelets were stimulated with 4μM of ADP, there was an eightfold increase In the number of available binding sites for human fibrinogen, with affinity constant of 1.9 x 109M-1. This striking increase in fibrinogen receptor sites on human platelets was specific for ADP as contrasted to ATP, AMP, and adenosine. Prostacyclin (Prostaglandin I2, PGI2), a novel prostaglandin produced by the blood vessel wall, completely blocked this ADP-induced increase in fibrinogen receptor sites on human platelets. The effect of PGI2 was prompt and concentration dependent, reaching maximum at 10-9M. 6-keto PGF2 a stable derivative ot PGI2, did not have such an effect. Thus movement of fibrinogen receptor sites on human platelet membrane stimulated with ADP is prevented by PGI2. This represents a new biologic property of this vascular hormone and contributes to better understanding of its potent inhibitory effect in vitro and in vivo on ADP-induced platelet aggregation requiring mobilization of fibrinogen receptor.

Effect of acute experimental colitis on rabbit colonic smooth muscle

1986 ◽  
Vol 251 (4) ◽  
pp. G538-G545 ◽  
Author(s):  
J. D. Cohen ◽  
H. W. Kao ◽  
S. T. Tan ◽  
J. Lechago ◽  
W. J. Snape
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Current Pulse ◽  
Mechanical Response ◽  
Contractile Activity ◽  
Experimental Colitis ◽  
Isometric Tension ◽  
Mucosal Inflammation ◽  
Resting Membrane Potential ◽  
Circular Smooth Muscle

The membrane potential and contractile activity of colonic circular smooth muscle from New Zealand White rabbits were studied after the production of acute experimental colitis. Colitis was induced in the distal colon by rectal infusion of formaldehyde solution, followed by an intravenous bolus of soluble immune complexes. Despite active mucosal inflammation, there are only occasional inflammatory cells in the muscularis. Electrophysiological studies on tissue from control rabbits and rabbits with colitis were performed using double sucrose gap and intracellular microelectrode techniques. The resting membrane potential was lower (-44 +/- 3 mV) in muscle from rabbits with colitis compared with control animals (-54 +/- 2 mV) (P less than 0.02). Amplitude of the electrotonic potential after a hyperpolarizing current pulse was decreased (P less than 0.05) and the time constant was shortened (P less than 0.01) in muscle from animals with colitis compared with normal animals. Amplitude (13.1 +/- 2.3 mV) and maximum rate of rise (0.24 +/- 0.06 V/s) of the spike potential, initiated by a depolarizing current pulse, were decreased in muscle from animals with colitis compared with muscle from healthy animals (P less than 0.001). Isometric tension generation after electrical and chemical depolarization of the membrane or bethanechol administration was decreased (P less than 0.001) in muscle from colitic animals. These studies suggest 1) membrane resistance and membrane potential are decreased in muscle strips from animals with colitis; and 2) there is a disturbance in the electrical and mechanical response of these tissues after stimulation.

Effects of bethanechol and the octapeptide of cholecystokinin on colonic smooth muscle in the cat

1987 ◽  
Vol 252 (5) ◽  
pp. G654-G661
Author(s):  
W. J. Snape ◽  
S. T. Tan ◽  
H. W. Kao
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Slow Wave ◽  
Spike Activity ◽  
Membrane Resistance ◽  
Wave Pattern ◽  
Isometric Tension ◽  
Muscle Membrane ◽  
Maximum Effect ◽  
Smooth Muscle Membrane

The aim of this study is to compare the action of the cholinergic agonist, bethanechol, with the action of the octapeptide of cholecystokinin (CCK-OP) on feline circular colonic smooth muscle membrane potential and isometric tension, using the double sucrose gap. Depolarization of the membrane greater than 10 mV by K+ or bethanechol increased tension and spontaneous spike activity. CCK-OP (10(-9) M) depolarized the membrane (6.1 +/- 1.3 mV) without an increase in tension or spike activity. Depolarization of the membrane by increasing [K+]o was associated with a decrease in the membrane resistance. The slow-wave duration (2.3 +/- 0.2 s) was unchanged by administration of K+ or bethanechol but was prolonged after increasing concentrations of CCK-OP. The maximum effect occurred at a 10(-10) M concentration of CCK-OP (4.5 +/- 0.4 s, P less than 0.01). At higher concentrations of CCK-OP (greater than 10(-10) M), the slow-wave pattern became disorganized. Addition of increasing concentrations of [K+]o or bethanechol, but not CCK-OP, stimulated a concentration-dependent increase in the maximum rate of rise (dV/dtmax) of an evoked spike potential. These studies suggest 1) bethanechol decreased the membrane potential without altering the slow-wave activity, whereas CCK-OP has a minimal effect on the membrane potential but distorted the slow-wave shape; 2) an increased amplitude of the spike and dV/dtmax of the spike were associated with an increase in phasic contractions after bethanechol or increased [K+]o; 3) the lack of an increase in the spike amplitude and the dV/dtmax to CCK-OP was associated with no increase in phasic contraction.

Glomerular endothelin receptors during initiation and maintenance of ischemic acute renal failure in rats

1991 ◽  
Vol 260 (1) ◽  
pp. F110-F118
Author(s):  
B. M. Wilkes ◽  
A. R. Pearl ◽  
P. F. Mento ◽  
M. E. Maita ◽  
C. M. Macica ◽  
...  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Acid Treatment ◽  
Affinity Constant ◽  
Left Renal Artery ◽  
Sprague Dawley ◽  
Receptor Sites ◽  
Sprague Dawley Rats ◽  
Receptor Number ◽  
Ischemic Acute Renal Failure

Glomerular endothelin (ET) receptors were studied in normal Sprague-Dawley rats and in rats with ischemic acute renal failure (ARF) induced by a 60-min occlusion of the left renal artery (right kidney intact). In normal rats ET bound to specific glomerular receptor sites [equilibrium affinity constant (Kd), 46.6 +/- 5.8 pM; receptor number (Ro), 1,167 +/- 160 fmol/mg (n = 7)]. ET infusion (90 ng.kg-1.min-1, intra-arterially) raised mean arterial pressure by 32 +/- 4 mmHg, lowered renal blood flow (RBF) by 62% and glomerular filtration rate (GFR) by 49%, and reduced the number of glomerular ET receptor sites by 62%. Reduced ET binding could not be explained by prior occupancy, because acid treatment (which dissociates bound ET from its receptors) did not increase receptor number. If elevated ET levels contributed to decreased RBF and GFR in ARF, glomerular ET receptors would be expected to down-regulate. In rats with ischemic ARF there were no differences in the number or affinity of glomerular ET receptors in the clamped or contralateral kidneys. Additional studies demonstrated that the downregulation response to ET infusion was intact in ARF. The data demonstrate that glomerular ET receptors are unaltered in ischemic ARF and do not support a role for increased glomerular ET in the alterations of renal hemodynamics in this model.

scholarly journals Topography and dynamics of receptors for acetylated and malondialdehyde-modified low-density lipoprotein in the plasma membrane of mouse peritoneal macrophages as visualized by colloidal gold in conjunction with surface replicas.

1984 ◽  
Vol 32 (10) ◽  
pp. 1017-1027 ◽  
Author(s):  
H Robenek ◽  
G Schmitz ◽  
G Assmann
Keyword(s):  
Plasma Membrane ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Peritoneal Macrophages ◽  
Carbon Surface ◽  
Low Density ◽  
Double Labeling ◽  
Ldl Receptors ◽  
Receptor Sites ◽  
Mouse Peritoneal Macrophages

The topography and dynamics of receptors for acetylated (acetyl) and malondialdehyde-modified (MDA) low-density lipoprotein (LDL) in the plasma membrane of cultured mouse peritoneal macrophages were investigated using a new technique. Modified LDL labeled with gold particles was used to visualize LDL receptors in the plane of the plasma membrane in platinum-carbon surface replicas of critical point-dried cells. It was found that the native distribution of unoccupied acetyl-LDL receptors is diffuse, whereas unoccupied MDA-LDL receptors are preclustered in the plasma membrane. Competition and double labeling experiments suggest the existence of two distinct classes of receptor sites for acetyl-LDL and MDA-LDL.

Quantitative analysis of blood vessel permeability of squirrel monkeys

1991 ◽  
Vol 260 (4) ◽  
pp. H1194-H1204 ◽  
Author(s):  
R. G. Tompkins
Keyword(s):  
Transport Model ◽  
Low Density Lipoprotein ◽  
Effective Diffusion ◽  
Density Lipoprotein ◽  
Vascular Wall ◽  
Squirrel Monkeys ◽  
Regression Methods ◽  
Ldl Transport ◽  
Ldl Uptake

A mathematical transport model was derived to analyze in vivo low-density lipoprotein (LDL) transport across the aorta, peripheral muscular arteries, and major veins of squirrel monkeys (primates that develop diet-induced atherosclerosis similar to humans). Parameters determining the relative magnitudes of intimal permeability and diffusion within the vascular wall were optimized by nonlinear regression methods. Transmural LDL concentrations demonstrating discrete spatial resolution along the endothelial surface were previously obtained after 30 min of tracer circulation using quantitative autoradiography. In this study, intimal mass transfer coefficient (k1) was determined in 87 vascular regions representing 280 transmural profiles. As a result of this analysis, the value of k1 was 1.7 +/- 0.4 x 10(-9) cm/s for arteries, 2.9 +/- 0.3 x 10(-9) cm/s for veins, and 60 +/- 120 x 10(-9) cm/s for enhanced LDL uptake regions, which was a significant increase (P less than 0.01). The effective diffusion coefficient was 6.2 +/- 3.7 x 10(-10) cm2/s for all vascular regions examined. As a result of this analysis, focal regions of enhanced LDL uptake were explained solely on the basis of intimal permeability.

scholarly journals LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Xunde Xian ◽  
Yinyuan Ding ◽  
Marco Dieckmann ◽  
Li Zhou ◽  
Florian Plattner ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Vascular Wall ◽  
Cholesterol Homeostasis ◽  
Cell Surface Receptor ◽  
Wide Range ◽  
Surface Receptor

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor with diverse physiological roles, ranging from cellular uptake of lipoproteins and other cargo by endocytosis to sensor of the extracellular environment and integrator of a wide range of signaling mechanisms. As a chylomicron remnant receptor, LRP1 controls systemic lipid metabolism in concert with the LDL receptor in the liver, whereas in smooth muscle cells (SMC) LRP1 functions as a co-receptor for TGFβ and PDGFRβ in reverse cholesterol transport and the maintenance of vascular wall integrity. Here we used a knockin mouse model to uncover a novel atheroprotective role for LRP1 in macrophages where tyrosine phosphorylation of an NPxY motif in its intracellular domain initiates a signaling cascade along an LRP1/SHC1/PI3K/AKT/PPARγ/LXR axis to regulate and integrate cellular cholesterol homeostasis through the expression of the major cholesterol exporter ABCA1 with apoptotic cell removal and inflammatory responses.

scholarly journals Scavenger Receptor CD36 Directs Nonclassical Monocyte Patrolling Along the Endothelium During Early Atherogenesis

2017 ◽  
Vol 37 (11) ◽  
pp. 2043-2052 ◽  
Author(s):  
Paola M. Marcovecchio ◽  
Graham D. Thomas ◽  
Zbigniew Mikulski ◽  
Erik Ehinger ◽  
Karin A.L. Mueller ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Fold Increase ◽  
Vascular Wall ◽  
Western Diet ◽  
Oxidized Lipoprotein

Objective— Nonclassical monocytes (NCM) function to maintain vascular homeostasis by crawling or patrolling along the vessel wall. This subset of monocytes responds to viruses, tumor cells, and other pathogens to aid in protection of the host. In this study, we wished to determine how early atherogenesis impacts NCM patrolling in the vasculature. Approach and Results— To study the role of NCM in early atherogenesis, we quantified the patrolling behaviors of NCM in ApoE −/− (apolipoprotein E) and C57BL/6J mice fed a Western diet. Using intravital imaging, we found that NCM from Western diet–fed mice display a 4-fold increase in patrolling activity within large peripheral blood vessels. Both human and mouse NCM preferentially engulfed OxLDL (oxidized low-density lipoprotein) in the vasculature, and we observed that OxLDL selectively induced NCM patrolling in vivo. Induction of patrolling during early atherogenesis required scavenger receptor CD36, as CD36 −/− mice revealed a significant reduction in patrolling activity along the femoral vasculature. Mechanistically, we found that CD36-regulated patrolling was mediated by a SFK (src family kinase) through DAP12 (DNAX activating protein of 12KDa) adaptor protein. Conclusions— Our studies show a novel pathway for induction of NCM patrolling along the vascular wall during early atherogenesis. Mice fed a Western diet showed increased NCM patrolling activity with a concurrent increase in SFK phosphorylation. This patrolling activity was lost in the absence of either CD36 or DAP12. These data suggest that NCM function in an atheroprotective manner through sensing and responding to oxidized lipoprotein moieties via scavenger receptor engagement during early atherogenesis.

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