• BMB Reports
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• 제56권5호
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• pp.314-319
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• 2023

Sepsis is a life-threatening multi-organ dysfunction with high mortality caused by the body's improper response to microbial infection. No new effective therapy has emerged that can adequately treat patients with sepsis. We previously demonstrated that interferon-β (IFN-β) protects against sepsis via sirtuin 1-(SIRT1)-mediated immunosuppression. Another study also reported its significant protective effect against acute respiratory distress syndrome, a complication of severe sepsis, in human patients. However, the IFN-β effect cannot solely be explained by SIRT1-mediated immunosuppression, since sepsis induces immunosuppression in patients. Here, we show that IFN-β, in combination with nicotinamide riboside (NR), alleviates sepsis by blocking endothelial damage via SIRT1 activation. IFN-β plus NR protected against cecal ligation puncture-(CLP)-induced sepsis in wild-type mice, but not in endothelial cell-specific Sirt1 knockout (EC-Sirt1 KO) mice. IFN-β upregulated SIRT1 protein expression in endothelial cells in a protein synthesis-independent manner. IFN-β plus NR reduced the CLP-induced increase in in vivo endothelial permeability in wild-type, but not EC-Sirt1 KO mice. IFN-β plus NR suppressed lipopolysaccharide-induced up-regulation of heparinase 1, but the effect was abolished by Sirt1 knockdown in endothelial cells. Our results suggest that IFN-β plus NR protects against endothelial damage during sepsis via activation of the SIRT1/heparinase 1 pathway.

• The Korean Journal of Physiology and Pharmacology
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• 제3권6호
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• pp.587-595
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• 1999

This study was designed to investigate effects of calcium antagonists on endothelial and neuronal dysfunction of right coronary artery (RCA) induced by ischemia- reperfusion in anesthetized, open-chest pigs. After reperfusion, pigs were sacrificed and the RCA was rapidly dissected for in vitro experiments. Experimental groups were divided into 4 groups: control (C-RCA), ischemia-reperfusion only (I-RCA), verapamil infusion (VI-RCA) and nifedipine infusion (NI-RCA) group, respectively. The ischemia did not affect hemodynamics, mean arterial pressure, heart rate, LVdP/dtmax, and decreased RCA flow. Arterial pressure and heart rate during ischemia-reperfusion were decreased in VI-RCA and NI-RCA, and RCA flow during reperfusion was increased in NI-RCA. 5-Hydroxytryptamine (5-HT) produced concentration-dependent contractions in C-RCA. The 5-HT-induced contractions were potentiated in I-RCA and VI-RCA, but not in NI-RCA. Endothelium-dependent relaxation by calcium ionophore A23187 was inhibited in I-RCA and VI-RCA, and recovered in NI-RCA. Cyclic GMP contents were decreased in I-RCA group alone. Electrical field stimulation in C-RCA produced transient and frequency-dependent contractions and at 50 Hz caused biphasic contractions. The transient contractions were not affected by pretreatment with phentolamine and atropine, but the biphasic contraction was altered by the pretreatment. Both contractions were inhibited in I-RCA, and were partially recovered in VI-RCA and NI-RCA. Ischemia-reperfusion of RCA in pigs causes endothelial and neuronal dysfunctions, and calcium antagonists partially prevent both.

• The Korean Journal of Physiology and Pharmacology
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• 제18권2호
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• pp.95-101
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• 2014

Cardiovascular disease is the prime cause of morbidity and mortality and the population ages that may contribute to increase in the occurrence of cardiovascular disease. Arginase upregulation is associated with impaired endothelial function in aged vascular system and thus may contribute to cardiovascular disease. According to recent research, Korean Red Ginseng water extract (KRGE) may reduce cardiovascular disease risk by improving vascular system health. The purpose of this study was to examine mechanisms contributing to age-related vascular endothelial dysfunction and to determine whether KRGE improves these functions in aged mice. Young ($10{\pm}3$ weeks) and aged ($55{\pm}5$ weeks) male mice (C57BL/6J) were orally administered 0, 10, or 20 mg/mouse/day of KRGE for 4 weeks. Animals were sacrificed and the aortas were removed. Endothelial arginase activity, nitric oxide (NO) generation and reactive oxygen species (ROS) production, endothelial nitric oxide synthase (eNOS) coupling, vascular tension, and plasma peroxynitrite production were measured. KRGE attenuated arginase activity, restored nitric oxide (NO) generation, reduced ROS production, and enhanced eNOS coupling in aged mice. KRGE also improved vascular tension in aged vessels, as indicated by increased acetylcholine-induced vasorelaxation and improved phenylephrine-stimulated vasoconstriction. Furthermore, KRGE prevented plasma peroxynitrite formation in aged mice, indicating reduced lipid peroxidation. These results suggest KRGE exerts vasoprotective effects by inhibiting arginase activity and augmenting NO signaling and may be a useful treatment for age-dependent vascular diseases.

• 대한한방내과학회지
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• 제29권3호
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• pp.657-665
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• 2008

Objectives : The objective of this study was to assess the effect of acupuncture applied at the ST36 point on blood pressure and endothelial dependent vasodilation in hypertensive patients. Methods : 24 hypertensive patients were recruited and randomized to a study group (12 subjects) or a control group (12 subjects). Both groups took FMD (endothelial-dependant, flow-mediated dilation) measurement and then acupuncture needles were inserted at ST36 for the study group. In the control group, they took sham acupuncture as a control. FMD was rechecked after 10-min acupuncture treatment. Blood pressure was measured before and after acupuncture treatment. Results : FMD increased significantly in the study group after acupuncture (9.5${\pm}$2.0% to 11.1${\pm}$2.2%), but not in the control group. In both groups, there were no changes in blood pressure and heart rate. Conclusions : Acupuncture on ST36 appears to improve endothelial dysfunction of hypertensive patients and this might result from inducing activation of endothelium-derived nitric oxide.

• BMB Reports
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• 제43권9호
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• pp.584-592
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• 2010

Tetrahydrobiopterin (BH4) is a multifunctional cofactor of aromatic amino acid hydroxylases and nitric oxide synthase (NOS) as well as an intracellular antioxidant in animals. Through regulation of NOS activity BH4 plays a pivotal role not only in a variety of normal cellular functions but also in the pathogenesis of cardiovascular and neurodegenerative diseases, which develop under oxidative stress conditions. It appears that a balanced interplay between BH4 and NOS is crucial for cellular fate. If cellular BH4 homeostasis maintained by BH4 synthesis and regeneration fails to cope with increased oxidative stress, NOS is uncoupled to generate superoxide rather than NO and, in turn, exacerbates impaired BH4 homeostasis, thereby leading to cell death. The fundamental biochemical events involved in the BH4-NOS interplay are essentially the same, as revealed in mammalian endothelial, cardiac, and neuronal cells. This review summarizes information on the cellular BH4 homeostasis in mammals, focusing on its regulation under normal and oxidative stress conditions.

• Journal of Pharmaceutical Investigation
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• 제23권1호
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• pp.1-9
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• 1993

The endothelial cell of brain capillary called the blood-brain barrier (BBB) has carrier-mediated transport systems for nutrients and drugs. The mechanism of the BBB transport of basic and acidic drugs has been reviewed and examined for endogenous transport systems in BBB in WKY and SHRSP. Acidic drugs such as salicylic acid and basic drugs such as eperisone are taken up in a carrier mediated manner through the BBB via the monocarboxylic acid and amine transport systems. The specific dysfunction for the choline transport at the BBB in SHRSP would affect the function of the brain endothelial cell and brain parenchymal cell. The utilization of the endogenous transport systems of monocarboxylic acid and amine could be promising strategy for the effective drug delivery to the brain.

• Toxicological Research
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• 제30권3호
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• pp.141-148
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• 2014

Endothelium-derived relaxing factors (EDRFs), including nitric oxide (NO), prostacyclin ($PGI_2$), and endothelium-derived hyperpolarizing factor (EDHF), play pivotal roles in regulating vascular tone. Reduced EDRFs cause impaired endothelium-dependent vasorelaxation, or endothelial dysfunction. Impaired endothelium-dependent vasorelaxation in response to acetylcholine (ACh) is consistently observed in conduit vessels in human patients and experimental animal models of hypertension. Because small resistance arteries are known to produce more than one type of EDRF, the mechanism(s) mediating endothelium-dependent vasorelaxation in small resistance arteries may be different from that observed in conduit vessels under hypertensive conditions, where vasorelaxation is mainly dependent on NO. EDHF has been described as one of the principal mediators of endothelium-dependent vasorelaxation in small resistance arteries in normotensive animals. Furthermore, EDHF appears to become the predominant endothelium-dependent vasorelaxation pathway when the endothelial NO synthase (NOS3)/NO pathway is absent, as in NOS3-knockout mice, whereas some studies have shown that the EDHF pathway is dysfunctional in experimental models of hypertension. This article reviews our current knowledge regarding EDRFs in small arteries under normotensive and hypertensive conditions.

• IMMUNE NETWORK
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• 제15권4호
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• pp.206-211
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• 2015

Pulmonary edema is a major cause of mortality due to acute lung injury (ALI). The involvement of protein kinase C-${\delta}$ (PKC-${\delta}$) in ALI has been a controversial topic. Here we investigated PKC-${\delta}$ function in ALI using PKC-${\delta}$ knockout (KO) mice and PKC inhibitors. Our results indicated that although the ability to produce proinflammatory mediators in response to LPS injury in PKC-${\delta}$ KO mice was similar to that of control mice, they showed enhanced recruitment of neutrophils to the lung and more severe pulmonary edema. PKC-${\delta}$ inhibition promoted barrier dysfunction in an endothelial cell layer in vitro, and administration of a PKC-${\delta}$-specific inhibitor significantly increased steady state vascular permeability. A neutrophil transmigration assay indicated that the PKC-${\delta}$ inhibition increased neutrophil transmigration through an endothelial monolayer. This suggests that PKC-${\delta}$ inhibition induces structural changes in endothelial cells, allowing extravasation of proteins and neutrophils.

• BMB Reports
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• 제47권10호
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• pp.552-557
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• 2014

The main purpose of this study was to investigate whether type 3 muscarinic acetylcholine receptor (M3R) dysfunction induced vascular hyperpermeability. Transwell system analysis showed that M3R inhibition by selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and small interfering RNA both increased endothelial permeability. Using coimmunoprecipitation and Western blot assay, we found that M3R inhibition increased VE-cadherin and ${\beta}$-catenin tyrosine phosphorylation without affecting their expression. Using PTP1B siRNA, we found that PTP1B was required for maintaining VE-cadherin and ${\beta}$-catenin protein dephosphorylation. In addition, 4-DAMP suppressed PTP1B activity by reducing cyclic adenosine monophosphate (cAMP), but not protein kinase $C{\alpha}$ ($PKC{\alpha}$). These data indicate that M3R preserves the endothelial barrier function through a mechanism potentially maintaining PTP1B activity, keeping the adherens junction proteins (AJPs) dephosphorylation.

• The Korean Journal of Physiology and Pharmacology
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• 제15권3호
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• pp.123-128
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• 2011

Caesalpinia sappan (C. sappan) is a medicinal plant used for promoting blood circulation and removing stasis. During a screening procedure on medicinal plants, the ethylacetate extract of the lignum of C. sappan (CLE) showed inhibitory activity on arginase which has recently been reported as a novel therapeutic target for the treatment of cardiovascular diseases such as atherosclerosis. CLE inhibited arginase II activity prepared from kidney lysate in a dose-dependent manner. In HUVECs, inhibition of arginase activity by CLE reciprocally increased NOx production through enhancement of eNOS dimer stability without any significant changes in the protein levels of eNOS and arginase II expression. Furthermore, CLE-dependent arginase inhibition resulted in increase of NO generation and decrease of superoxide production on endothelium of isolated mice aorta. These results indicate that CLE augments NO production on endothelium through inhibition of arginase activity, and may imply their usefulness for the treatment of cardiovascular diseases associated with endothelial dysfunction.