GLP-1 receptor (GLP-1R) agonists may improve endothelial function (EF) via metabolic improvement and direct vascular action. The current study determined the effect of GLP-1R agonist exenatide on postprandial EF in type 2 diabetes and the mechanisms underlying GLP-1R agonist–mediated vasodilation. Two crossover studies were conducted: 36 participants with type 2 diabetes received subcutaneous exenatide or placebo for 11 days and EF, and glucose and lipid responses to breakfast and lunch were determined; and 32 participants with impaired glucose tolerance (IGT) or diet-controlled type 2 diabetes had EF measured before and after intravenous exenatide, with or without the GLP-1R antagonist exendin-9. Mechanisms of GLP-1R agonist action were studied ex vivo on human subcutaneous adipose tissue arterioles and endothelial cells. Subcutaneous exenatide increased postprandial EF independent of reductions in plasma glucose and triglycerides. Intravenous exenatide increased fasting EF, and exendin-9 abolished this effect. Exenatide elicited eNOS activation and NO production in endothelial cells, and induced dose-dependent vasorelaxation and reduced high-glucose or lipid-induced endothelial dysfunction in arterioles ex vivo. These effects were reduced with AMPK inhibition. In conclusion, exenatide augmented postprandial EF in subjects with diabetes and prevented high-glucose and lipid-induced endothelial dysfunction in human arterioles. These effects were largely direct, via GLP-1R and AMPK activation.
Light chain amyloidosis (AL) involves overproduction of amyloidogenic light chain proteins (LC) leading to heart failure, yet the mechanisms underlying tissue toxicity remain unknown. We hypothesized that LC induces endothelial dysfunction in non-AL human microvasculature and apoptotic injury in human coronary artery endothelial cells (HCAECs). Adipose arterioles (n = 34, 50 ± 3 yr) and atrial coronary arterioles (n = 19, 68 ± 2 yr) from non-AL subjects were cannulated. Adipose arteriole dilator responses to acetylcholine/papaverine were measured at baseline and 1 h exposure to LC (20 μg/ml) from biopsy-proven AL subjects (57 ± 11 yr) without and with antioxidant cotreatment. Coronary arteriole dilation to bradykinin/papaverine was measured post-LC exposure. HCAECs were exposed to 1 or 24 h of LC. LC reduced dilation to acetylcholine (10(-4) M: 41.6 ± 7 vs. 85.8 ± 2.2% control, P < 0.001) and papaverine (81.4 ± 4.6 vs. 94.8 ± 1.3% control, P < 0.01) in adipose arterioles and to bradykinin (10(-6) M: 68.6 ± 6.2 vs. 90.9 ± 1.6% control, P < 0.001) but not papaverine in coronary arterioles. There was an increase in superoxide and peroxynitrite in arterioles treated with LC. Adipose arteriole dilation was restored by cotreatment with polyethylene glycol-superoxide dismutase and tetrahydrobiopterin but only partially restored by mitoquinone (mitochondria-targeted antioxidant) and gp91ds-tat (NADPH oxidase inhibitor). HCAECs exposed to LC showed reduced NO and increased superoxide, peroxynitrite, annexin-V, and propidium iodide compared with control. Brief exposure to physiological amounts of LC induced endothelial dysfunction in human adipose and coronary arterioles and increased apoptotic injury in coronary artery endothelial cells likely as a result of oxidative stress, reduced NO bioavailability, and peroxynitrite production. Microvascular dysfunction and injury is a novel mechanism underlying AL pathobiology and is a potential target for therapy.
Background The function of medin, one of the most common human amyloid proteins that accumulates in the vasculature with aging, remains unknown. We aim to probe medin's role in cerebrovascular disease by comparing cerebral arterial medin content between cognitively normal and vascular dementia (VaD) patients and studying its effects on endothelial cell ( EC ) immune activation and neuroinflammation. We also tested whether monosialoganglioside‐containing nanoliposomes could reverse medin's adverse effects. Methods and Results Cerebral artery medin and astrocyte activation were measured and compared between VaD and cognitively normal elderly brain donors. EC s were exposed to physiologic dose of medin (5 μmol/L), and viability and immune activation (interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) were measured without or with monosialoganglioside‐containing nanoliposomes (300 μg/ mL ). Astrocytes were exposed to vehicle, medin, medin‐treated EC s, or their conditioned media, and interleukin‐8 production was compared. Cerebral collateral arterial and parenchymal arteriole medin, white matter lesion scores, and astrocyte activation were higher in VaD versus cognitively normal donors. Medin induced EC immune activation (increased interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) and reduced EC viability, which were reversed by monosialoganglioside‐containing nanoliposomes. Interleukin‐8 production was augmented when astrocytes were exposed to medin‐treated EC s or their conditioned media. Conclusions Cerebral arterial medin is higher in VaD compared with cognitively normal patients. Medin induces EC immune activation that modulates astrocyte activation, and its effects are reversed by monosialoganglioside‐containing nanoliposomes. Medin is a candidate novel risk factor for aging‐related cerebrovascular disease and VaD.
Medin causes human microvascular endothelial dysfunction through oxidative and nitrative stress and promotes pro-inflammatory signaling in endothelial cells. These effects appear to be mediated via RAGE. The findings represent a potential novel mechanism of vascular injury.
Light chain amyloidosis (AL) is a plasma cell dyscrasia associated with production of amyloidogenic immunoglobulin light chains (LC). Despite its often fatal course, the mechanism of injury remains unknown. We tested the hypothesis that AL is associated with oxidative stress by comparing serum protein carbonyl (a marker of protein oxidation and oxidative stress) in AL subjects (n=23, 60±11 years) vs. controls (n=9, 54± 2 years); we also measured superoxide production (n=11) and dilator response to sodium nitroprusside (SNP, n=6) in isolated non-AL human adipose arterioles exposed to LC (20 μg/mL) purified from AL subjects for 1 h vs. control. Protein carbonyl was higher in AL patients (0.19±0.04 vs. 0.003±0.003 nmol/mg control, p=0.002). Post-exposure to LC proteins, arteriole superoxide was higher (1.89±0.36 times control, p=0.03) with impaired dilation to SNP (10 −4 M, 54±6 vs. 86±4%, p=0.01, logEC50 −3.7±0.2 vs. −6.7±0.6, p=0.002). AL is associated with systemic oxidative stress and brief acute exposure to AL light chain proteins induces oxidative stress and microvascular dysfunction in human adipose arterioles. This novel mechanism of injury may be important in AL pathophysiology. KeywordsAmyloid; Heart failure; Microvascular dysfunction; Oxidative stress; Reactive oxygen species; CardiomyopathyThe mechanism underlying multiorgan dysfunction from light chain amyloidosis (AL) is unknown but exposure of rodent tissue to light chain proteins (LC) purified from AL patients results in oxidative stress [1,2]. We tested the hypothesis that AL is associated with systemic protein oxidation and that acute exposure to LC induces human arteriolar oxidative stress and microvascular dysfunction. First, we compared serum protein carbonyl (marker of protein oxidation/oxidative stress [3]) in 23 AL patients (all biopsy-proven AL, 60±11 years, 10 males) to those of 9 healthy subjects (54±2 years, 5 males) by dinitrophenylhydrazine ELISA (Biocell Corp., Papatoetoe, NZ) and found higher levels in AL (Fig. 1A). From 3 AL patients, we isolated and purified urine LC using dialysis, size-specific filtration (Amikon spin columns 50/30/5KD) and lyophilization. They were verified as kappa LC by Western
The aggregation and fibril deposition of amyloid proteins have been implicated in a range of neurodegenerative and vascular diseases, and yet the underlying molecular mechanisms are poorly understood. Here, we use a combination of cell-based assays, biophysical analysis, and atomic force microscopy to investigate the potential involvement of oxidative stress in aortic medial amyloid (AMA) pathogenesis and deposition. We show that medin, the main constituent of AMA, can induce an environment rich in oxidative species, increasing superoxide and reducing bioavailable nitric oxide in human cells. We investigate the role that this oxidative environment may play in altering the aggregation process of medin and identify potential posttranslational modification sites where site-specific modification and interaction can be unambiguously demonstrated. In an oxidizing environment, medin is nitrated at tyrosine and tryptophan residues, with resultant effects on morphology that lead to longer fibrils with increased toxicity. This provides further motivation to investigate the role of oxidative stress in AMA pathogenicity.
Background: Light chain amyloidosis (AL) is a rare plasma cell dyscrasia associated with poor survival especially in the setting of heart failure. Late gadolinium enhancement (LGE) on cardiac MRI was recently found to correlate with myocardial amyloid deposition but the prognostic role is not established. The aim is to determine the prognostic significance of LGE in AL by comparing long term survival of AL patients with and without LGE.
We tested whether nanoliposomes containing phosphatidylcholine, cholesterol and phosphatidic acid (NLPA) prevent bamyloid 1-42 (Ab42) fibrillation and Ab42-induced human arteriole endothelial dysfunction. NLPA abolished Ab42 fibril formation (thioflavin-T fluorescence/electron microscopy). In ex-vivo human adipose and leptomeningeal arterioles, Ab42 impaired dilator response to acetylcholine that was reversed by NLPA; this protection was abolished by L-NGnitroarginine methyl ester. Ab42 reduced human umbilical vein endothelial cell NO production that was restored by NLPA. Nanoliposomes prevented Ab42 amyloid formation, reversed Ab42-induced human microvascular endothelial dysfunction and may be useful in Alzheimer's disease.
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