Abstract
Nitroglycerin (NTG) markedly enhances nitric oxide (NO) bioavailability. However, its ability to mimic the anti-inflammatory properties of NO remains unknown. Here, we examined whether NTG can suppress endothelial cell (EC) activation during inflammation and developed NTG nanoformulation to simultaneously amplify its anti-inflammatory effects and ameliorate adverse effects associated with high-dose NTG administration. Our findings reveal that NTG significantly inhibits human U937 cell adhesion to NO-deficient human microvascular ECs in vitro through an increase in endothelial NO and decrease in endothelial ICAM-1 clustering, as determined by NO analyzer, microfluorimetry, and immunofluorescence staining. Nanoliposomal NTG (NTG-NL) was formulated by encapsulating NTG within unilamellar lipid vesicles (DPhPC, POPC, Cholesterol, DHPE-Texas Red at molar ratio of 6:2:2:0.2) that were ~155 nm in diameter and readily uptaken by ECs, as determined by dynamic light scattering and quantitative fluorescence microscopy, respectively. More importantly, NTG-NL produced a 70-fold increase in NTG therapeutic efficacy when compared with free NTG while preventing excessive mitochondrial superoxide production associated with high NTG doses. Thus, these findings, which are the first to reveal the superior therapeutic effects of an NTG nanoformulation, provide the rationale for their detailed investigation for potentially superior vascular normalization therapies.
Highlights
Loss of endothelium-derived nitric oxide (NO), which prevents leukocyte-endothelial cell (EC) adhesion, is strongly implicated in chronic inflammation associated with debilitating cardiovascular conditions such as pulmonary arterial hypertension (PAH)[1], atherosclerosis[2], and diabetes[3]
Since NTG enhances endothelial NO. Bioavailability through both spontaneous biotransformation and endothelial NO synthase (eNOS) activation[7,8], we asked whether NTG could mimic the anti-inflammatory property of NO
Images of fluorescently-labeled adherent U937 cells and their quantification revealed that addition of NTG to L-NIO-treated ECs produces a dose-dependent inhibition of U937 cell adhesion to ECs (Fig. 1A,B), with the inhibition being significant (p < 0 .01) at 5 μ M NTG dose where U937 cell adhesion was comparable with that on untreated ECs
Summary
Loss of endothelium-derived nitric oxide (NO), which prevents leukocyte-endothelial cell (EC) adhesion, is strongly implicated in chronic inflammation associated with debilitating cardiovascular conditions such as pulmonary arterial hypertension (PAH)[1], atherosclerosis[2], and diabetes[3]. Our previous work has shown that incorporation of genistein within polymeric nanoparticles improves its anti-inflammatory effect by over two orders of magnitude[15]. Such a nanotherapeutic approach has the ability to amplify the potential anti-inflammatory effects of NTG as well as ameliorate the adverse effects associated with contemporary high-dose NTG administration. We developed a new nanoencapsulation approach for effective NTG delivery that exhibits potent anti-inflammatory effects at a dose 70-fold lower than that of free NTG while preventing excessive mitochondrial superoxide production associated with high NTG doses
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