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Endosomolytic Nano-Polyplex Platform Technology for Cytosolic Peptide Delivery To Inhibit Pathological Vasoconstriction.
Evans BC, Hocking KM, Kilchrist KV, Wise ES, Brophy CM, Duvall CL
(2015) ACS Nano 9: 5893-907
MeSH Terms: Cells, Cultured, Coronary Vasospasm, Cytosol, Drug Delivery Systems, Humans, Muscle, Smooth, Vascular, Nanostructures, Nanotechnology, Oligopeptides, Polymers, Vasoconstriction
Show Abstract · Added March 14, 2018
A platform technology has been developed and tested for delivery of intracellular-acting peptides through electrostatically complexed nanoparticles, or nano-polyplexes, formulated from an anionic endosomolytic polymer and cationic therapeutic peptides. This delivery platform has been initially tested and optimized for delivery of two unique vasoactive peptides, a phosphomimetic of heat shock protein 20 and an inhibitor of MAPKAP kinase II, to prevent pathological vasoconstriction (i.e., vasospasm) in human vascular tissue. These peptides inhibit vasoconstriction and promote vasorelaxation by modulating actin dynamics in vascular smooth muscle cells. Formulating these peptides into nano-polyplexes significantly enhances peptide uptake and retention, facilitates cytosolic delivery through a pH-dependent endosomal escape mechanism, and enhances peptide bioactivity in vitro as measured by inhibition of F-actin stress fiber formation. In comparison to treatment with the free peptides, which were endowed with cell-penetrating sequences, the nano-polyplexes significantly increased vasorelaxation, inhibited vasoconstriction, and decreased F-actin formation in the human saphenous vein ex vivo. These results suggest that these formulations have significant potential for treatment of conditions such as cerebral vasospasm following subarachnoid hemorrhage. Furthermore, because many therapeutic peptides include cationic cell-penetrating segments, this simple and modular platform technology may have broad applicability as a cost-effective approach for enhancing the efficacy of cytosolically active peptides.
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11 MeSH Terms
From ST segments to endothelial pathophysiology: hypercholesterolemia and endothelial superoxide production.
Harrison DG
(2014) J Clin Invest 124: 473-5
MeSH Terms: Animals, Biomedical Research, Clinical Trials as Topic, Coronary Vasospasm, Endothelium, Vascular, History, 20th Century, History, 21st Century, Humans, Hypercholesterolemia, Inflammation, Oxidative Stress, Reactive Oxygen Species, Superoxides, Vascular Diseases
Show Abstract · Added March 31, 2015
As a young medical resident, I encountered a patient suffering from spontaneous coronary vasospasm and was puzzled by these dramatic alterations in vasomotion. This encounter piqued my interest in understanding the drivers of vascular reactivity. In a paper published in the JCI, my colleagues and I revealed a role for superoxide production in the vascular dysfunction associated with hypercholesterolemia. Subsequent work by our group and others has unveiled complex associations between ROS generation and vascular disease.
1 Communities
1 Members
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14 MeSH Terms
Therapeutic procedures for coronary vasospasm-induced polymorphic ventricular tachycardia.
Dresen WF, Wells QS, Maron DJ, McPherson JA
(2012) Ther Adv Cardiovasc Dis 6: 115-21
MeSH Terms: Angiotensin-Converting Enzyme Inhibitors, Calcium Channel Blockers, Coronary Vasospasm, Defibrillators, Implantable, Drug-Eluting Stents, Electrocardiography, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Prognosis, Risk Factors, Smoking Cessation, Tachycardia, Ventricular
Show Abstract · Added February 28, 2014
Coronary vasospasm is an unusual cause of angina and myocardial ischemia, with the potential to provoke acute myocardial infarction, malignant cardiac arrhythmias, and sudden cardiac death. The diagnosis is largely clinical and requires a high index of suspicion. Provocation studies are rarely performed due to the risks of the procedure and the relatively low incidence of disease. A subset of patients does not respond to conventional medical therapy and a paucity of evidence exists to guide therapy. While generally believed a multifocal phenomenon, there have been reports of successful treatment of focal, refractory vasospasm with coronary stent implantation. Furthermore, consideration of an implantable cardioverter defibrillator is warranted when vasospasm is complicated by lethal ventricular arrhythmias.
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12 MeSH Terms
Serotonin and experimental vascular disease.
Heistad DD, Harrison DG, Armstrong ML
(1987) Int J Cardiol 14: 205-12
MeSH Terms: Animals, Arteriosclerosis, Blood Platelets, Cerebrovascular Circulation, Coronary Vasospasm, Macaca fascicularis, Platelet Aggregation, Serotonin, Splanchnic Circulation
Show Abstract · Added December 10, 2013
We have examined effects of atherosclerosis on constrictor responses to serotonin in several vascular beds. In normal monkeys, serotonin produces modest constriction of large arteries. In atherosclerotic monkeys, vasoconstrictor responses to serotonin are greatly potentiated in the limb, cerebral, and mesenteric circulation. The findings may be pertinent to the pathogenesis of vasospasm, which is an important complication of atherosclerosis. Platelets release serotonin when they aggregate. If platelets aggregate at atherosclerotic lesions and release serotonin, and vasoconstrictor responses to serotonin are greatly potentiated in atherosclerotic arteries, serotonin may be an important mediator of vasospasm. To determine whether treatment of atherosclerosis alters vascular responses, atherosclerotic monkeys were fed a low-cholesterol diet for 18 months. This treatment produced marked improvement in vascular lesions, but maximal vasodilator responses were not consistently improved by treatment of atherosclerosis. We speculated that fibrosis of the vessel may prevent improvement of vasodilator responses in vessels with fixed lesions. In contrast, we have found recently that dietary treatment of atherosclerosis abolishes hyperresponsiveness to serotonin in the limb. We conclude that atherosclerosis potentiates vasoconstrictor responses to serotonin and these abnormalities are reversible by dietary treatment of atherosclerosis.
1 Communities
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9 MeSH Terms
Increased adventitial mast cells in a patient with coronary spasm.
Forman MB, Oates JA, Robertson D, Robertson RM, Roberts LJ, Virmani R
(1985) N Engl J Med 313: 1138-41
MeSH Terms: Adult, Angina Pectoris, Variant, Cell Count, Coronary Angiography, Coronary Vasospasm, Coronary Vessels, Death, Sudden, Histamine Release, Humans, Male, Mast Cells, Prostaglandin D2, Prostaglandins D, SRS-A
Added December 10, 2013
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14 MeSH Terms