Shatin, Hong Kong
Shatin, Hong Kong

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Liu L.,Institute of Vascular Medicine | Liu J.,Institute of Vascular Medicine | Wong W.T.,Institute of Vascular Medicine | Tian X.Y.,Institute of Vascular Medicine | And 12 more authors.
Hypertension | Year: 2012

Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor, inhibits the inactivation and degradation of glucagon like peptide 1 (GLP-1), which is used for the treatment of type 2 diabetes mellitus. However, little is known about the role of GLP-1 in hypertension. This study investigated whether the activation of GLP-1 signaling protects endothelial function in hypertension. Two-week sitagliptin treatment (10 mg/kg per day, oral gavage) improved endothelium-dependent relaxation in renal arteries, restored renal blood flow, and reduced systolic blood pressure in spontaneously hypertensive rats. In vivo sitagliptin treatment elevated GLP-1 and GLP-1 receptor expressions, increased cAMP level, and subsequently activated protein kinase A, liver kinase B1, AMP-activated protein kinase-α and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-α, or NO synthase reversed the protective effects of sitagliptin. We also demonstrate that GLP-1 receptor agonist exendin 4 in vitro treatment had similar vasoprotective effects in spontaneously hypertensive rat renal arteries and increased NO production in spontaneously hypertensive rat aortic endothelial cells. Studies using transient expressions of wild-type and dominant-negative AMP-activated protein kinase-α2 support the critical role of AMP-activated protein kinase-α in mediating the effect of GLP-1 in endothelial cells. Ex vivo exendin 4 treatment also improved endothelial function of renal arteries from hypertensive patients. Our results elucidate that upregulation of GLP-1 and related agents improve endothelial function in hypertension by restoring NO bioavailability, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events. © 2012 American Heart Association, Inc.


Liu L.,Peking University | Liu J.,Institute of Vascular Medicine | Gao Y.,Peking University | Ng C.F.,Chinese University of Hong Kong | And 3 more authors.
Journal of Hypertension | Year: 2015

Objective: Glucagon-like peptide-1 (GLP-1) exerts its actions via activating GLP-1 receptor (GLP-1R). Our previous study showed a reduced GLP-1R expression in spontaneously hypertensive rat (SHR) renal arteries. The present study investigated the mechanisms underlying GLP- 1R downregulation in hypertension. Methods: Intrarenal arteries of normotensive Wistar-Kyoto rat (WKY) and SHR were suspended in the myograph for force measurement. GLP-1R expression was evaluated by both immunofluorescence and western blotting. Protein kinase Ca (PKCa), PKCb, PKCd, and total PKC levels were assayed by western blotting. Results: Immunofluorescence revealed reduced GLP-1R level in SHR renal arteries compared with WKY renal arteries. GLP-1R agonist exendin-4 induced concentrationdependent relaxations in WKY arteries, which mainly depended on the presence of endothelium. GLP-1R antagonist exendin 9-39 inhibited this relaxation in WKY arteries, whereas the relaxations were significantly less in SHR arteries. Ex-vivo treatment with PKC inhibitor GFX, PKCa and PKCb inhibitor Go 6976, and PKCb inhibitor hispidin but not PKCd inhibitor rottlerin improved the impaired relaxations and restored the diminished GLP-1R expression in SHR arteries. Furthermore, PKCb level was greater in SHR than WKY arteries, with no difference in PKCa, PKCd, or total PKC expressions between two rat strains. Treatment with PKC-activating agent phorbol-12- myristate-13-acetate attenuated exendin-4-induced relaxations and reduced GLP-1R expression in WKY arteries, which were reversed by GFX, Go 6976, or hispidin. More relevantly, immunofluorescence of human renal arteries also showed a reduced GLP-1R level in hypertensive patients. Conclusion: The present results provide novel evidence that the reduced GLP-1R expression in SHR renal arteries is most likely mediated through PKCb upregulation; the latter probably contributes to the impaired GLP-1Rmediated vasorelaxations in hypertension. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Xu T.-Y.,Shanghai JiaoTong University | Sun J.P.,Chinese University of Hong Kong | Lee A.P.-W.,Chinese University of Hong Kong | Yang X.S.,Chinese University of Hong Kong | And 7 more authors.
International Journal of Cardiology | Year: 2014

Background: Two-dimensional speckle tracking echocardiography (2DSTE) has been used widely in research, but rarely in clinical practice because data acquisition and analysis are time-consuming. By reducing the acquisition and analysis time, 3-dimensional STE may improve clinical impact. We investigated the feasibility of 3DSTE myocardial deformation, with comparison to 2DSTE. Methods: Transthoracic 3DSTE and 2DSTE were performed in 230 adults (138 men, 51 ± 14 years, and 142 hypertension, 10 heart failure and 78 normotensive subjects). The variables of LV deformation were analyzed using EchoPAC software. Results: The 3D LV longitudinal (LS) analysiswas feasible in 84.9% of the study subjects,whichwas lower than the 2D analysis (97.2%). The success rates for circumferential strain (CS) and radial strain (RS) were similar between the 2D and 3D techniques. All magnitude of strains measured by 2DSTE and 3DSTE were significantly correlated. The magnitude of 3D LS and CS was lower, but the 3D RS is higher than that of 2DSTE (-18.5±2.8 vs.-21.2± 3.5; 20.8 ± 4.1 vs. 21.7; and 50.0 ± 11.2 vs. 37.7 ± 12.6, respectively). Strains measured by 3DSTE exhibited stronger correlationwith LV ejection fraction (EF) than that by 2DSTE. In inter- and intra-observer reproducibility for 3D LS, CS, RS and AS were acceptable. The mean time of analysis for LV volume, EF and strains was 116 s by 3DSTE, which was significantly shorter than that by 2DSTE (5 min, P < 0.0001). Conclusions: Three-dimensional STE is feasible and reproducible in the estimation of LV function, requires substantially less time than 2DSTE and is a more feasible technique for LV function assessment in clinical practice. © 2014 Elsevier Ireland Ltd. All rights reserved.


Dong J.,Institute of Vascular Medicine | Wong S.L.,Institute of Vascular Medicine | Lau C.W.,Institute of Vascular Medicine | Liu J.,Institute of Vascular Medicine | And 9 more authors.
Kidney International | Year: 2013

Cardiovascular risks increase in postmenopausal women. While vitamin D is supplemented for osteoporosis, it is not known whether it protects renal arterial function during estrogen deficiency. Here we measured changes in renovascular reactivity induced by ovariectomy in rats and examined whether calcitriol, the most active form of vitamin D, was able to correct such changes. The impairment of endothelium-dependent relaxation in renal arteries from ovariectomized rats was effectively reversed by long-term calcitriol treatment. It was also corrected by acute exposure to cyclooxygenase-2 (COX-2) inhibitors and a thromboxane-prostanoid receptor antagonist, respectively. Calcitriol normalized the overexpression of COX-2 and thromboxane-prostanoid receptors in intralobal renal artery segments and aortic endothelial cells isolated from ovariectomized rats. In vitro exposure of the arterial segments to calcitriol for 12 h improved relaxation and downregulated thromboxane-prostanoid receptors. The attenuated nitric oxide production in ovariectomized rat aortic endothelial cells was restored following a 12-h treatment with calcitriol, COX-2 inhibition, or thromboxane-prostanoid receptor antagonism. Thus, impaired endothelium-dependent renal artery relaxation in ovariectomized rats is mediated largely through increased activity and expression of COX-2 and the thromboxane-prostanoid receptor. Calcitriol restores endothelial function through downregulating both signaling proteins during estrogen deficiency. © 2013 International Society of Nephrology.


Wong S.L.,Institute of Vascular Medicine | Wong S.L.,Chinese University of Hong Kong | Lau C.W.,Institute of Vascular Medicine | Wong W.T.,Institute of Vascular Medicine | And 8 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective- The purpose of this study was to examine the hypothesis that angiotensin II (Ang II) induced endothelial cyclooxygenase-2 (COX-2) expression, which in turn mediated the generation of proinflammatory cytokines. Methods and Results- Western blot analysis on primary rat endothelial cells showed Ang II induced COX-2 expression, which was abolished by cotreatment of p38 mitogen-activated protein kinase (SB 202190) and extracellular signal-regulated kinase 1/2 (PD 98059) inhibitors. Protein kinase Cδ (PKCδ) inhibitor (rottlerin) prevented extracellular signal-regulated kinase 1/2 phosphorylation and COX-2 expression. The pivotal role of PKCδ was further supported by a similar stimulatory effect of the PKC activator on COX-2 expression, signified by Ang II-stimulated translocation of PKCδ to the plasma membrane, and confirmed by PKCδ phosphorylation at Tyr311. Small interfering RNA targeting PKCδ diminished COX-2 expression, which was further abrogated by SB 202190. Human mesenteric arteries incubated with Ang II showed increased levels of endothelial COX-2 and monocyte chemoattractant protein-1; the former was inhibited by SB 202190 plus rottlerin, whereas the latter was prevented by COX-2 inhibitor. Conclusion- The present study pinpoints a novel role of PKCδ in Ang II-induced endothelial COX-2 upregulation and identifies a COX-2-dependent proatherosclerotic cytokine monocyte chemoattractant protein-1. The findings raise the possibility of curtailing endothelial COX-2 expression as a means of limiting or preventing vascular inflammation. Copyright © 2011 American Heart Association. All rights reserved.


Wong W.T.,Institute of Vascular Medicine | Wong W.T.,Chinese University of Hong Kong | Tian X.Y.,Institute of Vascular Medicine | Tian X.Y.,Chinese University of Hong Kong | And 10 more authors.
Antioxidants and Redox Signaling | Year: 2010

The mechanisms underlying the effect of the renin-angiotensin-aldosterone system (RAAS) inhibition on endothelial dysfunction in type 2 diabetes are incompletely understood. This study explored a causal relationship between RAAS activation and oxidative stress involved in diabetes-associated endothelial dysfunction. Daily oral administration of valsartan or enalapril at 10mg/kg/day to db/db mice for 6 weeks reversed the blunted acetylcholine-induced endothelium-dependent dilatations, suppressed the upregulated expression of angiotensin II type 1 receptor (AT1R) and NAD(P)H oxidase subunits (p22phox and p47phox), and reduced reactive oxygen species (ROS) production. Acute exposure to AT1R blocker losartan restored the impaired endothelium-dependent dilatations in aortas of db/db mice and also in renal arteries of diabetic patients (fasting plasma glucose level ≥7.0 mmol/l). Similar observations were also made with apocynin, diphenyliodonium, or tempol treatment in db/db mouse aortas. DHE fluorescence revealed an overproduction of ROS in db/db aortas which was sensitive to inhibition by losartan or ROS scavengers. Losartan also prevented the impairment of endothelium-dependent dilatations under hyperglycemic conditions that were accompanied by high ROS production. The present study has identified an initiative role of AT1R activation in mediating endothelial dysfunction of arteries from db/db mice and diabetic patients. © 2010 Mary Ann Liebert, Inc.


Qu D.,Institute of Vascular Medicine | Qu D.,Chinese University of Hong Kong | Liu J.,Institute of Vascular Medicine | Liu J.,Chinese University of Hong Kong | And 4 more authors.
Vascular Pharmacology | Year: 2014

The characteristics of endothelium-dependent relaxations in response to insulin and acetylcholine (ACh) in the mouse posterior tibial artery (PTA) were studied on wire myograph, and compared to those in the mouse main mesenteric artery (MMA). Insulin-induced relaxation in PTA was reversed by PI3K and Akt inhibitors, LY294002 and triciribine, but not by nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) or guanylate cyclase inhibitor, ODQ. The relaxation in PTA was also inhibited by apamin (small-conductance Ca2+-activated K+ channel blocker) plus charybdotoxin (intermediate-conductance Ca2+-activated K+ channel blocker), elevated KCl or ouabain (Na+-K+ ATPase inhibitor) plus BaCl2 [inwardly rectifying K+ (KIR) channel inhibitor]; whereas L-NAME but not triciribine inhibited ACh-induced relaxation in PTA. On the other hand, nitric oxide and endothelium-derived hyperpolarizing factor albeit to a less extent mediated both insulin- and ACh-induced relaxations in MMA. The present study is for the first time dissecting out the components of endothelium-dependent relaxation in mouse PTA and suggesting differential responses to different agonists in distinctive blood vessels. © 2014 Elsevier Inc.


Chan Y.C.,Institute of Vascular Medicine | Chan Y.C.,Chinese University of Hong Kong | Leung F.P.,Institute of Vascular Medicine | Leung F.P.,Chinese University of Hong Kong | And 13 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Objective-: Selective estrogen receptor modulators (SERMs) inhibit constriction of mammalian conduit arteries. However, it is unknown whether SERMs at therapeutically achievable concentrations could reduce vascular tone in resistance arteries. The present study aimed to examine roles of Ca influx in endothelium and endothelial nitric oxide synthase (eNOS) activation in dilatations induced by raloxifene, a second-generation SERM in myogenically active arteries.Methods and results-: Small mesenteric arteries from Sprague-Dawley rats were isolated and mounted in a pressure myograph for measurement of changes in vessel diameter. [Ca]i images on native endothelial cells of intact arteries were determined by the fluorescence imaging technique, and phosphorylation of eNOS was assayed by Western blotting. Raloxifene (0.3 to 10 nmol/L) produced dilatations on established steady myogenic constriction. Female rat arteries dilated significantly more in response to raloxifene than male arteries. Raloxifene-induced dilatations of female arteries were blunted by N-nitro-l-arginine methyl ester but unaffected by 1400W, charybdotoxin plus apamin, wortmannin, or LY294002. Raloxifene (3 nmol/L) triggered rises in endothelial cell [Ca]i and increased eNOS phosphorylation at Ser1177. Both effects were greater in arteries from female rats than in arteries from male rats. Increases in endothelial cell [Ca]i and in eNOS phosphorylation were prevented by removal of extracellular Ca ions. Finally, ICI 182,780 did not affect the raloxifene-stimulated rise in endothelial cell [Ca]i, eNOS phosphorylation, and vasodilatations. Chronic raloxifene treatment reduced myogenic constriction in arteries from female but not male rats. Conclusion-: Raloxifene at therapeutically relevant concentrations inhibits myogenic constriction by an NO-dependent mechanism that causally involves the elevated [Ca]i in endothelial cells and subsequent eNOS activation. Raloxifene dilates resistance arteries more effectively in female rats, indicating its significant gender-related action on endothelial cells in microcirculation. © 2010 American Heart Association, Inc.


Yang C.,Chinese University of Hong Kong | Chen Z.Y.,Chinese University of Hong Kong | Wong S.L.,Institute of Vascular Medicine | Liu J.,Institute of Vascular Medicine | And 5 more authors.
Cardiovascular Research | Year: 2013

Aimsβ-Sitosterol has become a popular cholesterol-lowering functional food product worldwide. β-Sitosterol can be oxidized to β-sitosterol oxidation products (SOPs) during food processing. Little is known about the impact of SOPs and β-sitosterol on the functionality of arteries. This study investigated the effects of SOPs and β-sitosterol on vasorelaxation and the possible cellular mechanisms involved.Methods and resultsBy isometric tension measurement, SOPs but not β-sitosterol blunted relaxation induced by acetylcholine or Ca2+ ionophore A23187 in endothelium-intact aortae. SOPs-impaired vasorelaxation was completely reversed by cyclooxygenase (COX)-2 inhibitor DuP-697, whereas the reversal by COX-1 inhibitor SC-560 was only partial. Western blotting and immunohistochemistry showed that SOPs increased the protein expression of COX-2 but not COX-1 in the endothelium. Using dihydroethidium staining and electron paramagnetic resonance spin trapping techniques, SOPs were found to elevate the level of reactive oxygen species in rat aortic endothelial cells, and the effects were reversed by antioxidants tempol, tiron, or diphenylene iodonium. Consistently, these antioxidants reversed SOPs-induced impairment of endothelium-dependent relaxation. Up-regulation of COX-2 expression by SOPs was also reversed by tempol. Moreover, SOPs attenuated nitric oxide donor sodium nitroprusside-induced relaxation in endothelium-intact, but not endothelium-denuded rings, confirming that SOPs act on the endothelium. Interestingly, a thromboxane-prostanoid (TP) receptor blocker S18886 reversed SOPs-impaired vasorelaxation, suggesting the involvement of TP receptor in mediating the downstream effect. SOPs decreased cGMP production, and the effect could be reversed by inhibiting COX-2 or TP receptor.ConclusionThis study provides novel experimental evidence showing the harmful effects of SOPs on endothelial function. © 2012 The Author.


Wong W.T.,Institute of Vascular Medicine | Wong S.L.,Institute of Vascular Medicine | Tian X.Y.,Institute of Vascular Medicine | Huang Y.,Institute of Vascular Medicine
Journal of Cardiovascular Pharmacology | Year: 2010

Endothelial dysfunction plays a key role in the initiation of cellular events evolving into the development of vascular complications in diabetes and hypertension. Diminished production and function of endothelium-derived nitric oxide and other vasoprotective factors and/or the exaggerated production of proinflammatory and vasoconstrictors such as angiotensin II, endothelin-1, reactive oxygen species, and cyclooxygenase-derived metabolites of arachidonic acid eventually lead to endothelial dysfunction, resulting in elevated vascular tone which contributes to hypertension, vascular, and cardiac remodeling, culminating in microvascular, macrovascular, and renal damages. Specific therapies targeting reactive oxygen species using antioxidants and inhibitors of the rennin-angiotensin system or increasing endothelial nitric oxide synthase activity might assist to reverse endothelial dysfunction and thus reduce the related cardiovascular morbidity and mortality in diabetes and hypertension. © 2010 by Lippincott Williams & Wilkins.

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