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Fulltext CNDP1, NOS3, and MnSOD Polymorphisms as Risk Factors for Diabetic Nephropathy among Type 2 Diabetic Patients in Malaysia

Yahya MJ, Ismail PB, Nordin NB, Akim ABM, Binti Md Yusuf WS, Adam NLB, et al.

J Nutr Metab, 2019;2019:8736215.
PMID: 30719346 DOI: 10.1155/2019/8736215

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of nephropathy. The aim of this study was to investigate the association of a genetic polymorphism of carnosinase (CNDP1-D18S880 and -rs2346061), endothelial nitric oxide synthase (NOS3-rs1799983), and manganese superoxide dismutase (MnSOD-rs4880) genes with the development of diabetic nephropathy among Malaysian type 2 diabetic patients. A case-control association study was performed using 652 T2DM patients comprising 227 Malays (without nephropathy = 96 and nephropathy = 131), 203 Chinese (without nephropathy = 95 and nephropathy = 108), and 222 Indians (without nephropathy = 136 and nephropathy = 86). DNA sequencing was performed for the D18S880 of CNDP1, while the rest were tested using DNA Sequenom MassARRAY to identify the polymorphisms. DNA was extracted from the secondary blood samples taken from the T2DM patients. The alleles and genotypes were tested using four genetic models, and the best mode of inheritance was chosen based on the least p value. The rs2346061 of CNDP1 was significantly associated with diabetic nephropathy among the Indians only with OR = 1.94 and 95% CI = (1.76-3.20) and fitted best the multiplicative model, while D18S880 was associated among all the three major races with the Malays having the strongest association with OR = 2.46 and 95% CI = (1.48-4.10), Chinese with OR = 2.26 and 95% CI = (1.34-3.83), and Indians with OR = 1.77 and 95% CI = (1.18-2.65) in the genotypic multiplicative model. The best mode of inheritance for both MnSOD and NOS3 was the additive model. For MnSOD-rs4880, the Chinese had OR = 2.8 and 95% CI = (0.53-14.94), Indians had OR = 2.4 and 95% CI = (0.69-2.84), and Malays had OR = 2.16 and 95% CI = (0.54-8.65), while for NOS3-rs1799983, the Indians had the highest risk with OR = 3.16 and 95% CI = (0.52-17.56), followed by the Chinese with OR = 3.55 and 95% CI = (0.36-35.03) and the Malays with OR = 2.89 and 95% CI = (0.29-28.32). The four oxidative stress-related polymorphisms have significant effects on the development of nephropathy in type 2 diabetes patients. The genes may, therefore, be considered as risk factors for Malaysian subjects who are predisposed to T2DM nephropathy.

Matched MeSH terms: Nitric Oxide Synthase Type III
Fulltext 3',4'-dihydroxyflavonol ameliorates endoplasmic reticulum stress-induced apoptosis and endothelial dysfunction in mice

Lau YS, Mustafa MR, Choy KW, Chan SMH, Potocnik S, Herbert TP, et al.

Sci Rep, 2018 01 29;8(1):1818.
PMID: 29379034 DOI: 10.1038/s41598-018-19584-8

Endoplasmic reticulum (ER) stress has been implicated in the development of hypertension 3 through the induction of endothelial impairment. As 3',4'-dihydroxyflavonol (DiOHF) 4 reduces vascular injury caused by ischaemia/reperfusion or diabetes, and flavonols have been demonstrated to attenuate ER stress, we investigated whether DiOHF can protect mice from ER stress-induced endothelial dysfunction. Male C57BLK/6 J mice were injected with tunicamycin to induce ER stress in the presence or absence of either DiOHF or tauroursodeoxycholic acid (TUDCA), an inhibitor of ER stress. Tunicamycin elevated blood pressure and impaired endothelium-dependent relaxation. Moreover, in aortae there was evidence of ER stress, oxidative stress and reduced NO production. This was coincident with increased NOX2 expression and reduced phosphorylation of endothelial nitric oxide synthase (eNOS) on Ser1176. Importantly, the effects of tunicamycin were significantly ameliorated by DiOHF or TUDCA. DiOHF also inhibited tunicamycin-induced ER stress and apoptosis in cultured human endothelial cells (HUVEC). These results provide evidence that ER stress is likely an important initiator of endothelial dysfunction through the induction of oxidative stress and a reduction in NO synthesis and that DiOHF directly protects against ER stress- induced injury. DiOHF may be useful to prevent ER and oxidative stress to preserve endothelial function, for example in hypertension.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism
Endothelial nitric oxide synthase G894T gene polymorphism and response to skin reactive hyperemia

Rasool AH, Ghazali DM, Abdullah H, Halim AS, Wong AR

Microvasc Res, 2009 Sep;78(2):230-4.
PMID: 19481100 DOI: 10.1016/j.mvr.2009.05.005

Post occlusive skin reactive hyperemia (PORH) is a tool used to assess microcirculation. Endothelial nitric oxide synthase (eNOS) mediates nitric oxide (NO) production; polymorphism of the eNOS gene may affect response to the PORH process. This study aims to determine whether eNOS G894T gene polymorphism affects response to skin PORH. 230 normotensive male and females between 18 and 40 years participated in this cross-sectional study. 170 subjects were of the homozygous GG genotype, whereas 60 were of the GT genotype. Skin PORH was performed by occlusion of the upper arm at 200 mm Hg for 3 min. Skin perfusion and temperature were monitored before, during and after occlusion release using the laser Doppler fluximetry. There were no significant differences between genotypes in their baseline blood pressure, serum cholesterol, BMI and age. Maximum change in perfusion after occlusion release (PORHmax) for the GG and GT genotypes were not significantly different at 50.15+/-1.29 vs. 47.92+/-2.17 AU; ANCOVA, p=0.351. Peak perfusion (PORHpeak) were also not significantly different between the two genotypes (61.23+/-1.36 vs. 57.72+/-2.32 AU; p=0.169). Minimum baseline perfusion were however higher in the GG compared to the GT genotype (10.83+/-0.29 vs. 9.61+/-0.50, p=0.029). We conclude that microvascular reactivity, assessed by change in perfusion after temporary ischemia was not significantly different between the GG and GT genotypes of the eNOS G894T gene. eNOS 894T allele carriers however, have lower baseline perfusion compared to the homozygous G894 allele carrier.

Matched MeSH terms: Nitric Oxide Synthase Type III/genetics*
Blood pressure lowering effect of Ficus deltoidea var kunstleri in spontaneously hypertensive rats: possible involvement of renin-angiotensin-aldosterone system, endothelial function and anti-oxidant system

Azis NA, Agarwal R, Ismail NM, Ismail NH, Kamal MSA, Radjeni Z, et al.

Mol Biol Rep, 2019 Jun;46(3):2841-2849.
PMID: 30977084 DOI: 10.1007/s11033-019-04730-w

This study investigated the effects of a standardised ethanol and water extract of Ficus deltoidea var. Kunstleri (FDK) on blood pressure, renin-angiotensin-aldosterone system (RAAS), endothelial function and antioxidant system in spontaneously hypertensive rats (SHR). Seven groups of male SHR were administered orally in volumes of 0.5 mL of either FDK at doses of 500, 800, 1000 and 1300 mg kg- 1, or captopril at 50 mg kg- 1 or losartan at 10 mg kg- 1 body weight once daily for 4 weeks or 0.5 mL distilled water. Body weight, systolic blood pressures (SBP) and heart rate (HR) were measured every week. 24-hour urine samples were collected at weeks 0 and 4 for electrolyte analysis. At week 4, sera from rats in the control and 1000 mg kg- 1 of FDK treated groups were analyzed for electrolytes and components of RAAS, endothelial function and anti-oxidant capacity. SBP at week 4 was significantly lower in all treatment groups, including captopril and losartan, when compared to that of the controls. Compared to the controls, ACE activity and concentrations of angiotensin I, angiotensin II and aldosterone were lower whereas concentrations of angiotensinogen and angiotensin converting enzyme 2 were higher in FDK treated rats. Concentration of eNOS and total anti-oxidant capacity were higher in FDK treated rats. Urine calcium excretion was higher in FDK treated rats. In conclusion, it appears that ethanol and water extract of FDK decreases blood pressure in SHR, which might involve mechanisms that include RAAS, anti-oxidant and endothelial system.

Matched MeSH terms: Nitric Oxide Synthase Type III
Fulltext Expression of Endothelin-1 and Endothelial Nitric Oxide Synthase in Normal and Preeclamptic Placentae

Khaing A, Swe AT, Aung CL, Thwin MM, Sein MT

Rev Bras Ginecol Obstet, 2022 Feb;44(2):125-132.
PMID: 35213910 DOI: 10.1055/s-0042-1742317

OBJECTIVE: To investigate the expression of endothelin-1 (ET-1) and endothelial nitric oxide (NO) synthase (eNOS) in normal and preeclamptic (PE) placentae.
METHODS: The present cross-sectional analytical study was performed in normal and PE primigravidae (n = 10 in each group) who were admitted to the North Okkalapa General and Teaching Hospital from February 2019 to February 2020. Serum samples were collected immediately before delivery, and placental tissues were collected immediately after emergency or elective cesarean section. The expression of placental eNOS was measured by western blot, and the levels of ET-1 in placental tissue homogenates and in the serum were measured by enzyme-linked immunosorbent assay (ELISA).
RESULTS: The PE group had significantly higher serum levels of ET-1 (median: 116.56 pg/mL; IQR: 89.14-159.62 pg/mL) than the normal group (median: 60.02 pg/mL; IQR: 50.89-94.37 pg/mL) (p

Matched MeSH terms: Nitric Oxide Synthase Type III
Fulltext Clinacanthus nutans Leaves Extract Reverts Endothelial Dysfunction in Type 2 Diabetes Rats by Improving Protein Expression of eNOS

Azemi AK, Mokhtar SS, Rasool AHG

Oxid Med Cell Longev, 2020;2020:7572892.
PMID: 32879653 DOI: 10.1155/2020/7572892

Diabetes mellitus is associated with endothelial dysfunction; it causes progressive vascular damage resulting from an impaired endothelium-dependent vasorelaxation. In the diabetes state, presence of hyperglycemia and insulin resistance predisposes to endothelial dysfunction. Clinacanthus nutans, widely used as a traditional medicine for diabetes is reported to have hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory properties. However, the possibility of C. nutans affecting the vascular endothelial function in diabetes remains unclear. This study was aimed at evaluating the effects of C. nutans methanolic leaves extract (CNME) on endothelial function in a type 2 diabetes (T2DM) rat model. Sixty male Sprague-Dawley rats were divided into five groups (n = 12 per group): nondiabetic control, nondiabetic treated with four weeks of CNME (500 mg/kg/daily), untreated diabetic rats, diabetic treated with metformin (300 mg/kg/daily), and diabetic treated with CNME (500 mg/kg/daily). T2DM was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) to rats fed with high-fat diet (HFD). Endothelial-dependent and endothelial-independent relaxations and contractions of the thoracic aorta were determined using the organ bath. Aortic endothelial nitric oxide synthase (eNOS) expression was determined using Western blotting. Endothelial-dependent relaxation was reduced in diabetic rats. Both diabetic groups treated with CNME or metformin significantly improved the impairment in endothelium-dependent vasorelaxation; this was associated with increased expression of aortic eNOS protein. CNME- and metformin-treated groups also reduced aortic endothelium-dependent and aortic endothelium-independent contractions in diabetics. Both of these diabetic-treated groups also reduced blood glucose levels and increased body weight compared to the untreated diabetic group. In conclusion, C. nutans improves endothelial-dependent vasodilatation and reduces endothelial-dependent contraction, thus ameliorating endothelial dysfunction in diabetic rats. This may occur due to its effect on increasing eNOS protein expression.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism*
Model for type 2 diabetes exhibits changes in vascular function and structure due to vascular oxidative stress and inflammation

Azemi AK, Mokhtar SS, Hou LJ, Sharif SET, Rasool AHG

Biotech Histochem, 2021 Oct;96(7):498-506.
PMID: 32957845 DOI: 10.1080/10520295.2020.1823480

We used a type 2 diabetes rat model produced by a high fat diet (HFD) followed by low dose streptozotocin (STZ) to study diabetic vasculopathy. Animals were evaluated for early vascular structural changes, endothelial function, inflammation, lipid profile and oxidative stress. We used 20 male Sprague-Dawley rats divided equally into control and diabetic groups. Diabetic rats were fed an HFD for 4 weeks, injected intraperitoneally with STZ, then sacrificed at week 15. Aortic endothelial nitric oxide synthase (eNOS), aortic superoxide dismutase (SOD), endothelial-dependent and independent relaxation and contraction, intima-media thickness (IMT), malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) were measured. Histopathological characteristics also were assessed. Diabetic rats exhibited higher fasting blood glucose (FBG), low density lipoprotein, total cholesterol and triglycerides compared to the control group. Aortic endothelium-dependent relaxation due to acetylcholine (ACh) was lower, while aortic endothelium-dependent contraction due to calcium ionophore and endothelium-independent contraction due to phenylephrine (PE) were higher for the diabetic group. eNOS expression was lower in the diabetic group compared to controls. IMT and MDA levels were increased, while SOD activity was decreased in the diabetic group compared to controls. TNF-α was higher in the diabetic group than for controls. Our type 2 diabetes model exhibited endothelial dysfunction associated with early vascular structural changes, dyslipidemia, increased vascular oxidative stress, and inflammation. Therefore, the model is suitable for studying diabetic atherosclerosis.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism
Vitamin D deficiency attenuates endothelial function by reducing antioxidant activity and vascular eNOS expression in the rat microcirculation

Wee CL, Mokhtar SS, Banga Singh KK, Rasool AHG

Microvasc Res, 2021 Nov;138:104227.
PMID: 34324883 DOI: 10.1016/j.mvr.2021.104227

This study examined the effects of vitamin D deficiency on vascular function and tissue oxidative status in the microcirculation; and whether or not these effects can be ameliorated with calcitriol, the active vitamin D metabolite. Three groups (n = 10 each) of male Sprague Dawley rats were fed for 10 weeks with control diet (CR), vitamin D-deficient diet without (DR), or with oral calcitriol supplementation (0.15 μg/kg) for the last four weeks (DSR). After 10 weeks, rats were sacrificed; mesenteric arterial rings were studied using wire myograph. Oxidative stress biomarkers malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured in the mesenteric arterial tissue. Vascular protein expression of endothelial nitric oxide synthase (eNOS) was determined by Western blotting. Acetylcholine-induced endothelium-dependent relaxation of DR was lower than CR. eNOS expression and SOD activity were lower in mesenteric arterial tissue of DR compared to CR. Calcitriol supplementation to DSR did not ameliorate the above parameters; in fact, augmented endothelium-dependent contraction was observed. Serum calcium was higher in DSR compared to CR and DR. In conclusion, vitamin D deficiency impaired microvascular vasodilation, associated with eNOS downregulation and reduced antioxidant activity. Calcitriol supplementation to vitamin D-deficient rats at the dosage used augmented endothelium-dependent contraction, possibly due to hypercalcaemia.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism*
Fulltext Calcitriol Supplementation Ameliorates Microvascular Endothelial Dysfunction in Vitamin D-Deficient Diabetic Rats by Upregulating the Vascular eNOS Protein Expression and Reducing Oxidative Stress

Wee CL, Mokhtar SS, Singh KKB, Yahaya S, Leung SWS, Rasool AHG

Oxid Med Cell Longev, 2021;2021:3109294.
PMID: 33623633 DOI: 10.1155/2021/3109294

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.15 μg/kg) in the last four weeks (DDS) (10 rats each group). A nondiabetic rat group that received control diet was also included (NR). After 10 weeks, rats were sacrificed; mesenteric arterial rings with and without endothelium were studied using wire myograph. Western blotting of the mesenteric arterial tissue was performed to determine the protein expression of endothelial nitric oxide synthase (eNOS) enzyme. Antioxidant enzyme superoxide dismutase (SOD) activity and oxidative stress marker malondialdehyde (MDA) levels in the mesenteric arterial tissue were also measured. The DC group had significantly lower acetylcholine-induced relaxation and augmented endothelium-dependent contraction, with reduced eNOS expression, compared to NR rats. In mesenteric arteries of DD, acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent relaxations were lower than those in DC. Calcitriol supplementation in DDS restored endothelium-dependent relaxation. Mesenteric artery endothelium-dependent contraction of DD was greater than DC; it was not affected by calcitriol supplementation. The eNOS protein expression and SOD activity were significantly lower while MDA levels were greater in DD compared to DC; these effects were not observed in DDS that received calcitriol supplementation. In conclusion, vitamin D deficiency causes eNOS downregulation and oxidative stress, thereby impairing the vascular function and posing an additional risk for microvascular complications in diabetes. Calcitriol supplementation to diabetics with vitamin D deficiency could potentially be useful in the management of or as an adjunct to diabetes-related cardiovascular complications.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism*
Reduced nitric oxide-mediated relaxation and endothelial nitric oxide synthase expression in the tail arteries of streptozotocin-induced diabetic rats

Mokhtar SS, Vanhoutte PM, Leung SW, Suppian R, Yusof MI, Rasool AH

Eur J Pharmacol, 2016 Feb 15;773:78-84.
PMID: 26825543 DOI: 10.1016/j.ejphar.2016.01.013

Diabetes is associated with endothelial dysfunction, which is characterized by impaired endothelium-dependent relaxations. The present study aimed to examine the role of nitric oxide (NO), prostacyclin and endothelium-dependent hyperpolarization (EDH), in the relaxation of ventral tail arteries of rats under diabetic conditions. Relaxations of tail arteries of control and diabetic rats were studied in wire myograph. Western blotting and immunostaining were used to determine the presence of proteins. Acetylcholine-induced relaxations were significantly smaller in arteries of diabetic compared to control rats (Rmax; 70.81 ± 2.48% versus 85.05 ± 3.15%). Incubation with the combination of non-selective cyclooxygenase (COX) inhibitor, indomethacin and potassium channel blockers, TRAM 34 and UCL 1684, demonstrated that NO-mediated relaxation was attenuated significantly in diabetic compared to control rats (Rmax; 48.47 ± 5.84% versus 68.39 ± 6.34%). EDH-type (in the presence of indomethacin and NO synthase inhibitor, LNAME) and prostacyclin-mediated (in the presence of LNAME plus TRAM 34 and UCL 1684) relaxations were not significantly reduced in arteries of diabetic compared to control rats [Rmax: (EDH; 17.81 ± 6.74% versus 34.16 ± 4.59%) (prostacyclin; 15.85 ± 3.27% versus 17.23 ± 3.75%)]. Endothelium-independent relaxations to sodium nitroprusside, salbutamol and prostacyclin were comparable in the two types of preparations. Western blotting and immunostaining indicated that diabetes diminished the expression of endothelial NO synthase (eNOS), while increasing those of COX-1 and COX-2. Thus, since acetylcholine-induced NO-mediated relaxation was impaired in diabetes because of reduced eNOS protein expression, pharmacological intervention improving NO bioavailability could be useful in the management of diabetic endothelial dysfunction.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism*
Fulltext Piper sarmentosum increases nitric oxide production in oxidative stress: a study on human umbilical vein endothelial cells

Ugusman A, Zakaria Z, Hui CK, Nordin NA

Clinics (Sao Paulo), 2010 Jul;65(7):709-14.
PMID: 20668629 DOI: 10.1590/S1807-59322010000700010

Nitric oxide produced by endothelial nitric oxide synthase (eNOS) possesses multiple anti-atherosclerotic properties. Hence, enhanced expression of eNOS and increased Nitric oxide levels may protect against the development of atherosclerosis. Piper sarmentosum is a tropical plant with antioxidant and anti-inflammatory activities. This study aimed to investigate the effects of Piper sarmentosum on the eNOS and Nitric oxide pathway in cultured human umbilical vein endothelial cells (HUVECs).

Matched MeSH terms: Nitric Oxide Synthase Type III/physiology*
Baicalein impairs vascular tone in normal rat aortas: role of superoxide anions

Machha A, Achike FI, Mohd MA, Mustafa MR

Eur J Pharmacol, 2007 Jun 22;565(1-3):144-50.
PMID: 17442302

Acute exposure to the flavonoid baicalein inhibited endothelium-dependent relaxation in physiological arteries, although the mechanisms are not fully understood. We investigated the effect of baicalein on vascular tone in Wistar-Kyoto (WKY) rat isolated aortic rings in the presence and absence of oxidative stress to further determine the underlying mechanisms. Exposure to baicalein (10 microM) completely abolished endothelium-dependent relaxation induced by acetylcholine and attenuated significantly the endothelium-independent relaxation induced by sodium nitroprusside. Baicalein, similar to Nomega-nitro-L-arginine methyl ester (L-NAME, 10 microM), potentiated significantly the contractile response of aortic rings to alpha1-adrenoceptor agonist phenylephrine. In the presence of L-NAME the baicalein effect on phenylphrine contraction or acetylcholine relaxation was unaltered, suggesting that these effects of baicalein are (like L-NAME effect) endothelial nitric oxide synthase (eNOS)/endothelium-derived nitric oxide-dependent. Inhibition of cyclooxygenase activity with indomethacin (10 microM) or scavenging of superoxide anions with superoxide dismutase (150 units/ml), but not scavenging of hydrogen peroxide with catalase (800 units/ml), enhanced significantly by an essentially similar extent the relaxation to acetylcholine in baicalein-pretreated aortic rings. Relaxant effect to acetylcholine was significantly attenuated in control aortic rings, but was completely abolished in baicalein-pretreated aortic rings in the presence of reduced form of beta-nicotinamide adenine di-nucleotide (beta-NADH, 300 microM). Baicalein blocked beta-NADH (300 microM)-induced transient contractions, suggesting that baicalein may have inhibited activity of NADH/NADPH-oxidase. Baicalein did not alter the failure of acetylcholine to induce relaxation in the presence of pyrogallol (300 microM). In summary, acute exposure to baicalein impairs eNOS/endothelium-derived nitric oxide-mediated vascular tone in rat aortas through the inhibition of endothelium-derived nitric oxide bioavailability coupled to reduced bioactivity of endothelium-derived nitric oxide and to cyclooxygenase-mediated release of superoxide anions.

Matched MeSH terms: Nitric Oxide Synthase Type III/antagonists & inhibitors
Fulltext Endothelium-Dependent Relaxation Effect of Apocynum venetum Leaf Extract via Src/PI3K/Akt Signalling Pathway

Lau YS, Ling WC, Murugan D, Kwan CY, Mustafa MR

Nutrients, 2015 Jul;7(7):5239-53.
PMID: 26133970 DOI: 10.3390/nu7075220

Botanical herbs are consumed globally not only as an essential diet but also as medicines or as functional/recreational food supplements. The extract of the Apocynum venetum leaves (AVLE), also known as Luobuma, exerts its antihypertensive effect via dilating the blood vessels in an endothelium- and concentration-dependent manner with optimal effect seen at as low as 10 µg/mL. A commercial Luoboma "antihypertensive tea" is available commercially in the western province of China. The present study seeks to investigate the underlying cellular mechanisms of the nitric oxide (NO)-releasing property of AVLE in rat aortas and human umbilical vein endothelial cells (HUVECs). Endothelium-dependent relaxation induced by AVLE was assessed in organ chambers in the presence or absence of polyethyleneglycol catalase (PP2, 20 µM; inhibitor of Src kinase), wortmannin (30 nM) and LY294002 (20 µM; PI3 (phosphatidylinositol3)-Kinase inhibitor), N(G)-nitro-L-arginine (L-NAME, 100 µM; endothelial NO synthase inhibitor (eNOS)) and ODQ (1 µM; soluble guanylyl cyclase inhibitor). Total nitrite and nitrate (NOx) level and protein expression of p-Akt and p-eNOS were measured. AVLE-induced endothelium-dependent relaxation was reduced by PP2, wortmannin and LY294002 and abolished by L-NAME and ODQ. AVLE significantly increased total NOx level in rat aortas and in HUVECs compared to control. It also instigated phosphorylation of Akt and eNOS in cultured HUVECs in a concentration-dependent manner and this was markedly suppressed by PP2, wortmannin and LY294002. AVLE also inhibited superoxide generated from both NADPH oxidase and xanthine/xanthine oxidase system. Taken together, AVLE causes endothelium-dependent NO mediated relaxations of rat aortas through Src/PI3K/Akt dependent NO signalling pathway and possesses superoxide scavenging activity.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism
Effects of flavonoids on vascular smooth muscle of the isolated rat thoracic aorta

Ajay M, Gilani AU, Mustafa MR

Life Sci, 2003 Dec 19;74(5):603-12.
PMID: 14623031

The potency, structure-activity relationship, and mechanism of vasorelaxation of a series of flavonoids, representing different subclasses (flavonols: fisetin, rutin, quercetin; flavones: chrysin, flavone, baicalein; flavanones: naringenin, naringin; isoflavones: diadzein and flavanes: epigallo catechin gallate), were examined in the isolated rat aorta. Most of the flavonoids tested showed concentration dependent relaxant effects against K+ (80 mM) and phenylephrine (PE, 0.1 microM)-induced contractions with a greater inhibition of the responses to the alpha1-adrenoceptor agonist. The relaxant effects of most of the flavonoids involve in part the release of nitric oxide and prostaglandins from the endothelium as pretreatment with L-NAME and indomethacin attenuated the responses. In addition, the relaxant action of the flavonoids includes inhibition of Ca+2 influx and release of Ca+2 from intracellular stores. A structure-activity relationship amongst the flavonoids was suggested.

Matched MeSH terms: Nitric Oxide Synthase Type III
Direct effects of quercetin on impaired reactivity of spontaneously hypertensive rat aortae: comparative study with ascorbic acid

Ajay M, Achike FI, Mustafa AM, Mustafa MR

Clin Exp Pharmacol Physiol, 2006 Apr;33(4):345-50.
PMID: 16620299

1. There is a growing interest in the anti-oxidant characteristics and use of flavonoids in the management of cardiovascular diseases. The cardiovascular mechanism of action of these plant derivatives remains controversial. This study compared the effects of the flavonoid quercetin with those of the anti-oxidant vitamin ascorbic acid (vitamin C) on the reactivity of aortic rings from spontaneously hypertensive rats (SHR). 2. The phenylephrine (PE)-induced contractile and the endothelium-dependent and independent relaxant responses of aortic rings from 21 to 22 week old SHR and age-matched normotensive Wistar (WKY) rats were observed in the presence of quercetin or ascorbic acid. All the experiments were performed in the presence of the cyclooxygenase inhibitor, indomethacin (10 micromol/L). 3. The endothelium-dependent and independent relaxations to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were significantly lesser in the SHR compared to the WKY tissues whereas the contractile responses to PE were similar in both tissues. Pretreatment of WKY rings with quercetin or ascorbic acid had no effect on the responses to ACh or PE. In the SHR tissues, however, quercetin or ascorbic acid significantly improved the relaxation responses to ACh and reduced the contractions to PE with greater potency for quercetin. Both compounds lacked any effects on the responses to SNP in either aortic ring types. N(omega)-nitro-L-arginine methyl ester (l-NAME, 10 micromol/L) significantly attenuated the vasodepressor effects of quercetin and ascorbic acid, raising the responses to PE to a level similar to that observed in the control SHR tissues. In l-NAME pretreated aortic rings, quercetin and ascorbic acid inhibited the contractile responses to PE with the same magnitude in WKY and SHR tissues. 4. The present results suggest that acute exposure to quercetin improves endothelium-dependent relaxation and reduces the contractile responses of hypertensive aortae with a greater potency than ascorbic acid. This suggests a better vascular protection with this flavonoid than ascorbic acid in the SHR model of hypertension and possibly in human cardiovascular diseases.

Matched MeSH terms: Nitric Oxide Synthase Type III/antagonists & inhibitors
Fulltext Sodium nitrite exerts an antihypertensive effect and improves endothelial function through activation of eNOS in the SHR

Ling WC, Murugan DD, Lau YS, Vanhoutte PM, Mustafa MR

Sci Rep, 2016 09 12;6:33048.
PMID: 27616322 DOI: 10.1038/srep33048

Sodium nitrite (NaNO2) induces relaxation in isolated arteries partly through an endothelium-dependent mechanism involving NO-eNOS-sGC-cGMP pathway. The present study was designed to investigate the effect of chronic NaNO2 administration on arterial systolic blood pressure (SBP) and vascular function in hypertensive rats. NaNO2 (150 mg L-1) was given in drinking water for four weeks to spontaneously (SHR) and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) treated hypertensive SD rats. Arterial SBP and vascular function in isolated aortae were studied. Total plasma nitrate/nitrite and vascular cyclic guanosine monophosphate (cGMP) levels were measured using commercially available assay kits. Vascular nitric oxide (NO) levels were evaluated by DAF-FM fluorescence while the proteins involved in endothelial nitric oxide synthase (eNOS) activation was determined by Western blotting. NaNO2 treatment reduced SBP, improved the impaired endothelium-dependent relaxation, increased plasma total nitrate/nitrite level and vascular tissue NO and cGMP levels in SHR. Furthermore, increased presence of phosphorylated eNOS and Hsp-90 was observed in NaNO2-treated SHR. The beneficial effect of nitrite treatment was not observed in L-NAME treated hypertensive SD rats. The present study provides evidence that chronic treatment of genetically hypertensive rats with NaNO2 improves endothelium-dependent relaxation in addition to its antihypertensive effect, partly through mechanisms involving activation of eNOS.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism*
Fulltext Ficus deltoidea suppresses endothelial activation, inflammation, monocytes adhesion and oxidative stress via NF-κB and eNOS pathways in stimulated human coronary artery endothelial cells

Mohd Ariff A, Abu Bakar NA, Abd Muid S, Omar E, Ismail NH, Ali AM, et al.

BMC Complement Med Ther, 2020 Feb 17;20(1):56.
PMID: 32066426 DOI: 10.1186/s12906-020-2844-6

BACKGROUND: Ficus deltoidea (FD) has been shown to have antidiabetic, anti-inflammatory, antinociceptive and antioxidant properties. However, its effects on key events in the pathogenesis of atherosclerosis are unknown.
AIM: To investigate the endothelial activation, inflammation, monocyte-endothelial cell binding and oxidative stress effects of four FD varieties.
METHODS: Human coronary artery endothelial cells (HCAEC) were incubated with different concentrations of aqueous ethanolic extracts of FD var. trengganuensis (FDT), var. kunstleri (FDK), var. deltoidea (FDD) and var. intermedia (FDI), together with LPS. Protein and gene expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), interleukin-6 (IL-6), Nuclear factor-κB (NF-κB) p50 and p65 and endothelial nitric oxide synthase (eNOS) were measured using ELISA and QuantiGene plex, respectively. Adhesion of monocyte to HCAEC and formation of reactive oxygen species (ROS) were detected by Rose Bengal staining and 2'-7'-dichlorofluorescein diacetate (DCFH-DA) assay.
RESULTS: FDK exhibited the highest inhibition of biomarkers in relation to endothelial activation and inflammation, second in reducing monocyte binding (17.3%) compared to other varieties. FDK (25.6%) was also the most potent at decreasing ROS production.
CONCLUSION: FD has anti-atherogenic effects, possibly mediated by NF-κB and eNOS pathways; with FDK being the most potent variety. It is potentially beneficial in mitigating atherogenesis.

Matched MeSH terms: Nitric Oxide Synthase Type III
Fulltext Bee Bread Ameliorates Vascular Inflammation and Impaired Vasorelaxation in Obesity-Induced Vascular Damage Rat Model: The Role of eNOS/NO/cGMP-Signaling Pathway

Othman ZA, Zakaria Z, Suleiman JB, Nna VU, Che Romli A, Wan Ghazali WS, et al.

Int J Mol Sci, 2021 Apr 19;22(8).
PMID: 33921777 DOI: 10.3390/ijms22084225

Obesity and hyperlipidemia are major risk factors for developing vascular diseases. Bee bread (BB) has been reported to exhibit some biological actions, including anti-obesity and anti-hyperlipidemic. This study aims to investigate whether bee bread can ameliorate vascular inflammation and impaired vasorelaxation activity through eNOS/NO/cGMP pathway in obese rats. Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10/group), namely: control (normal group), obese rats (OB group), obese rats treated with bee bread (0.5 g/kg/day, OB/BB group) and obese rats treated with orlistat (10 mg/kg/day, OB/OR group). The latter three groups were given a high-fat diet (HFD) for 6 weeks to induced obesity before being administered with their respective treatments for another 6 weeks. After 12 weeks of the total experimental period, rats in the OB group demonstrated significantly higher Lee obesity index, lipid profile (total cholesterol, triglyceride, low-density lipoprotein), aortic proinflammatory markers (tumor necrosis factor-α, nuclear factor-κβ), aortic structural damage and impairment in vasorelaxation response to acetylcholine (ACh). Bee bread significantly ameliorated the obesity-induced vascular damage manifested by improvements in the lipid profile, aortic inflammatory markers, and the impaired vasorelaxation activity by significantly enhancing nitric oxide release, promoting endothelial nitric oxide synthase (eNOS) and cyclic guanosine monophosphate (cGMP) immunoexpression. These findings suggest that the administration of bee bread ameliorates the impaired vasorelaxation response to ACh by improving eNOS/NO/cGMP-signaling pathway in obese rats, suggesting its vascular therapeutic role.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism*
Quercetin/adenosine combination may induce insulin resistance in high fat diet-fed mice

Lee CY

Obes Res Clin Pract, 2012 Jan-Mar;6(1):e1-e90.
PMID: 24331176 DOI: 10.1016/j.orcp.2011.05.002

Quercetin and adenosine are natural antioxidants separately claimed to improve metabolic syndrome parameters. The effect of this combination (QA) was examined in high fat diet-fed mice. Results showed that growth and blood parameters, as observed for quercetin-treated mice, were not significantly different from the control. Adenosine alone caused hyperglycemia and reduced plasma adiponectin. QA feeding led to increased adiposity and circulatory insulin, and concomitantly down-regulated liver eNOS and LFABP expressions. This showed that interaction occurred between quercetin and adenosine, and combined ingestion may lead to insulin resistance, while adenosine does not prevent the development of metabolic syndrome.:

Matched MeSH terms: Nitric Oxide Synthase Type III
Fulltext Cystathione gamma lyase/Hydrogen Sulphide Pathway Up Regulation Enhances the Responsiveness of α1A and α1B-Adrenoreceptors in the Kidney of Rats with Left Ventricular Hypertrophy

Ahmad A, Sattar MA, Azam M, Abdulla MH, Khan SA, Hashmi F, et al.

PLoS One, 2016;11(5):e0154995.
PMID: 27191852 DOI: 10.1371/journal.pone.0154995

The purpose of the present study was to investigate the interaction between H2S and NO (nitric oxide) in the kidney and to evaluate its impact on the functional contribution of α1A and α1B-adrenoreceptors subtypes mediating the renal vasoconstriction in the kidney of rats with left ventricular hypertrophy (LVH). In rats the LVH induction was by isoprenaline administration and caffeine in the drinking water together with intraperitoneal administration of H2S. The responsiveness of α1A and α1B to exogenous noradrenaline, phenylephrine and methoxaminein the absence and presence of 5-methylurapidil (5-MeU) and chloroethylclonidine (CEC) was studied. Cystathione gamma lyase (CSE), cystathione β synthase (CBS), 3-mercaptopyruvate sulphar transferase (3-MST) and endothelial nitric oxide synthase (eNOS) were quantified. There was significant up regulation of CSE and eNOS in the LVH-H2S compared to the LVH group (P<0.05). Baseline renal cortical blood perfusion (RCBP) was increased (P<0.05) in the LVH-H2S compared to the LVH group. The responsiveness of α1A-adrenergic receptors to adrenergic agonists was increased (P<0.05) after administration of low dose 5-Methylurapidil in the LVH-H2S group while α1B-adrenergic receptors responsiveness to adrenergic agonists were increased (P<0.05) by both low and high dose chloroethylclonidine in the LVH-H2S group. Treatment of LVH with H2S resulted in up-regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways in the kidney. These up regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways enhanced the responsiveness of α1A and α1B-adrenoreceptors subtypes to adrenergic agonists in LVH-H2S. These findings indicate an important role for H2S in modulating deranged signalling in the renal vasculature resulting from LVH development.

Matched MeSH terms: Nitric Oxide Synthase Type III/metabolism

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