Publications by authors named "Hong Chai"

80 Publications

An elephant trunk stent graft strayed into the false lumen leading to a death during the Sun's operation: A case report.

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2021 Feb;46(2):217-220

Department of Cardiovascular Surgery, First Hospital of Lanzhou University, Lanzhou 730030.

Type A aortic dissection (AD) is a critical and severe disease with high mortality. The Sun's operation is a standard surgical method for this kind of disease at present. For the procedure, an elephant trunk stent is inserted into the true lumen of the descending aorta and the aortic arch is replaced. A patient was admitted to the First Hospital of Lanzhou University due to sudden chest and back pain for 6 days. Computed tomography angiography (CTA) showed type A AD. Ascending aorta replacement, Sun's operation, and ascending aorta to right femoral artery bypass grafting were performed. After surgery, the patient's condition was worsened. The digital subtraction angiography (DSA) showed the elephant trunk stent was inserted into the false lumen of AD, leading to the occlusion of the large blood vessel at the distal part of the abdominal aorta and below. Although we performed intima puncture and endovascular aortic repair, the patient was still dead.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2021.190608DOI Listing
February 2021

Inhibition of BAMBI reduces the viability and motility of colon cancer via activating TGF-β/Smad pathway and .

Oncol Lett 2021 Apr 2;21(4):244. Epub 2021 Feb 2.

[This retracts the article DOI: 10.3892/ol.2017.6811.].
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http://dx.doi.org/10.3892/ol.2021.12505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882889PMC
April 2021

Can Next-generation Sequencing Replace Fecal Immunochemical Tests or CT in the Screening of Colorectal Cancer and Advanced Adenoma?

J Coll Physicians Surg Pak 2020 09;30(9):940-945

Department of Gastroenterology, Renmin Hospital of Wuhan University, China.

Objective: To explore the feasibility of next-generation sequencing (NGS) for the screening of colorectal cancer (CRC) and advanced adenoma (AA).

Study Design: Observational study. Place and Duration of the Study: Renmin Hospital of Wuhan University, Wuhan, China, from June 2019 to February 2020.

Methodology: Patients who met inclusion and exclusion criteria were divided into three groups: CRC, AA, and control group. Then, the gene methylation status in the blood in the CRC, AA, and control group was analysed by NGS, and the CRC screening risk assessment model was used for comprehensive analysis. Afterwards, the methylated haplotype index (PHF Index) was calculated, and the screening results of the patients were classified as positive or negative, according to the score. The clinicopathological results were used as the gold standard, and the screening results for NGS were compared with the computed tomography (CT) and fecal immunochemical test (FIT) to text its feasibility.

Results: NGS has a certain detection ability for CRC, with a sensitivity of 57.1% (8/14). This was higher than that of FIT and CT, and the combined positive rate of these three methods could reach 92.3% (12/13). The sensitivity of detection of AA could reach up to 75.0% (6/8) after combining with FIT and CT. The positive rate of the NGS test for postoperative CRC was 23.1% (3/13), which was significantly lower than preoperative CRC. The sensitivity of CT for preoperative CRC detection was only 45.5% (5/11), but the specificity could reach up to 98.2% (55/56), which was higher than NGS (71/78, 91.0%) and FIT (27/33, 81.8%).

Conclusion: Although NGS cannot replace FIT and CT at present, this provides a new effective and auxiliary detection method for people who are unsuitable or unwilling to receive colonoscopy. Key Words: Colorectal neoplasms, Adenoma, High-throughput nucleotide sequencing, Mass screening, Fecal immunochemical tests, Computed tomography.
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http://dx.doi.org/10.29271/jcpsp.2020.09.940DOI Listing
September 2020

Association between IL12B polymorphisms and inflammatory bowel disease in Caucasian population: A meta-analysis.

Cytokine 2020 12 15;136:155296. Epub 2020 Sep 15.

Department of Gastroenterology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, China. Electronic address:

Background: Published studies on association between IL12B (G/A) rs10045431, (T/C)rs6887695 polymorphisms and inflammatory bowel disease (IBD) risk in Caucasian population have yielded conflicting results. The aim of this study was to potentially provide more reliable conclusions by conducting a meta-analysis.

Methods: Published studies concerned association between IL12B rs10045431, rs6887695 polymorphisms and IBD were searched from the Wiley Online Library, PubMed, Web of Science and the CNKI database. The odds ratio (OR) with 95% confidence interval (CI) was calculated to evaluate the strength of the relationship. The false positive report probabilities (FPRPs) test and trial sequential analysis (TSA) was performed to investigated the reliability of results.

Results: A total of 20 studies comprising 10761 Crohn's disease (CD), 10921 ulcerative colitis (UC) and 18381 controls were included in this meta-analysis. Overall, the pooled results showed that IL12B rs6887695 polymorphism significantly increased both CD and UC risk under all model, while IL12B rs10045431 polymorphism dramatically decreased both CD and UC risk under all model. FPRP and TSA demonstrated that above associations was confirmed in the present study.

Conclusion: The results of meta-analysis indicate IL12B rs10045431 and rs6887695 polymorphisms significantly associate with IBD in Caucasian population.
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http://dx.doi.org/10.1016/j.cyto.2020.155296DOI Listing
December 2020

Association between PTGER4 polymorphisms and inflammatory bowel disease risk in Caucasian: A meta-analysis.

Medicine (Baltimore) 2020 Aug;99(34):e19756

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei.

Background: The results from previous studies on association between prostaglandin E receptor 4 (PTGER4) polymorphisms and inflammatory bowel disease (IBD) risk in Caucasian were conflict. The present study aimed to investigate the genetic association by conducting a meta-analysis.

Methods: Systematic literature search was conducted through Wiley Online Library, Chinese National Knowledge Infrastructure (CNKI), and PubMed databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to investigate the associations between rs4613763 T/C, 17234657T/G polymorphisms, and IBD risk in Caucasian.

Results: Twenty case-control studies consisting of 18,495 Crohn disease (CD) patients and 4203 ulcerative colitis (UC) patients, as well as 26,063 controls were included in this meta-analysis. The rs4613763T/C polymorphism had obvious influence on CD, UC risk in Caucasian. However, rs17234657T/G polymorphism had obvious influence on CD but not UC in Caucasian.

Conclusion: This meta-analysis suggested that both the rs4613763 T/C, rs17234657T/G polymorphisms had obvious influence on risk of CD in Caucasian. In addition, rs4613763 T/C, polymorphism had obvious influence on risk of UC in Caucasian.
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http://dx.doi.org/10.1097/MD.0000000000019756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447366PMC
August 2020

Incidence of extrahepatic cancers among individuals with chronic hepatitis B or C virus infection: A nationwide cohort study.

J Viral Hepat 2020 09 18;27(9):896-903. Epub 2020 May 18.

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

This study examined the association between chronic HBV or HCV infection and the risk of extrahepatic cancers. A total of 537 103 adults aged ≥20 years without history of cancer were identified from the Korean National Health Insurance Service-National Sample Cohort between 2003 and 2013. The difference in cancer incidence was compared between those with and without chronic HBV or HCV infection. During 3 854 130 person-years of follow-up (median follow-up: 8.0 years), 19 089 participants developed cancer. After adjusting for sex, body mass index, smoking, drinking, income percentile, residential area and comorbidities, hazard ratios (HRs) for incident extrahepatic cancer were significantly higher in participants with chronic HBV infection (HR: 1.27, 95% confidence interval [CI]: 1.20-1.35), HCV infection (HR: 1.31, 95% CI: 1.16-1.48) or HBV/HCV dual infection (HR: 1.41, 95% CI: 1.31-1.72) compared to participants without HBV or HCV infection. In chronic HBV infection, the cancer risk was higher for haematologic malignancy [HR (95% CI) = 2.46 (1.92-3.15)], gallbladder [1.55 (1.05-2.29)], pancreas [1.52 (1.07-2.15)], stomach [1.39 (1.22-1.58)], lung [1.27 (1.04-1.55)], colorectum [1.21 (1.03-1.42)] and thyroid cancer [1.20 (1.05-1.36)]. In chronic HCV infection, the cancer risk was higher for testis [10.34 (1.35-79.78)], gallbladder [2.90 (1.62-5.18)], prostate [2.51 (1.65-3.82)] and thyroid cancer [1.46 (1.10-1.93)]. In conclusion, chronic HBV or HCV infection was not only associated with an increased risk of liver cancer, but also associated with an increased risk of multiple extrahepatic cancers.
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http://dx.doi.org/10.1111/jvh.13304DOI Listing
September 2020

Inhibition of BAMBI reduces the viability and motility of colon cancer via activating TGF-β/Smad pathway and .

Oncol Lett 2017 Oct 24;14(4):4793-4799. Epub 2017 Aug 24.

Department of Gastroenterology, The People's Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430060, P.R. China.

Colon cancer is a highly metastatic gastrointestinal cancer. BMP activin membrane-bound inhibitor (BAMBI), as a pseudo-receptor of the tumor growth factor (TGF)-β signal transduction pathway, has previously been demonstrated to be involved in human cancers. The present study demonstrated that BAMBI-small interfering (si)RNA regulated the viability and motility of colon cancer by activating TGF-β signaling. The expression level of BAMBI was suppressed by transfecting BAMBI-siRNA into the SW480 and HT-29 colon cancer cell lines. Decreased cell proliferation and increased cell apoptosis were detected in SW480 and HT-29 cells transfected with BAMBI-siRNA. Decreased expression of proliferation marker proteins Ki67 and proliferating cell nuclear antigen and elevated expression of apoptosis marker proteins (caspases-3, -8 and -9) further verified the role of BAMBI-siRNA in inhibiting cell viability. Silencing of BAMBI strongly reduced the closing rate and the number of invasive cells compared with control group. BAMBI-siRNA additionally resulted in decreased expression of migration marker proteins matrix metalloproteinase-9 (MMP-9), MMP-14 and vascular endothelial cell growth factor. In addition, the expression of TGF-β and phosphorylated-mothers against decapentaplegic homolog (Smad) 2/3 was increased in W480 and HT-29 cells transfected with BAMBI-siRNA. Elevated expression of the downstream signaling molecule E2F transcription factor 4/5 and suppressed c-MYC were additionally detected in the BAMBI-siRNA group. Finally, the experiment in the CSC xenograft revealed that BAMBI-siRNA strongly reduced the tumor growth and tumor volume. BAMBI-siRNA inhibited hepatic metastases and the expression of metastasis-associated proteins. The upregulated expression of TGF-β signaling proteins were detected in the BAMBI-siRNA group compared with control group . Overall, the results of the present study indicated that the inhibition of BAMBI reduces the viability and motility of colon cancer and may involve activation of the TGF-β/Smad pathway and .
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http://dx.doi.org/10.3892/ol.2017.6811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649694PMC
October 2017

Optimal threshold of stimulated serum thyroglobulin level for F-FDG PET/CT imaging in patients with thyroid cancer.

J Huazhong Univ Sci Technolog Med Sci 2017 Jun 6;37(3):429-432. Epub 2017 Jun 6.

Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.

This study was to explore the optimal threshold of thyroid-stimulating hormone (TSH)-stimulated serum thyroglobulin (s-Tg) for patients who were to receive F-fluorodeoxyglucose (F-FDG) PET/CT scan owing to clinical suspicion of differentiated thyroid cancer (DTC) recurrence but negative post-therapeutic I whole-body scan (I-WBS). A total of 60 qualified patients underwent PET/CT scanning from October 2010 to July 2014. The receiver operating characteristic (ROC) curve analyses showed that s-Tg levels over 49 μg/L led to the highest diagnostic accuracy of PET/CT to detect recurrence, with a sensitivity of 89.5% and a specificity of 90.9%. Besides, bivariate correlation analysis showed positive correlation between s-Tg levels and the maximum standardized uptake values (SUVmax) of F-FDG in patients with positive PET/CT scanning, suggesting a significant influence of TSH both on Tg release and uptake of F-FDG. So, positive PET/CT imaging is expected when patients have negative I-WBS but s-Tg levels over 49 μg/L.
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http://dx.doi.org/10.1007/s11596-017-1752-6DOI Listing
June 2017

Diagnostic value of Tg and TgAb for metastasis following ablation in patients with differentiated thyroid carcinoma coexistent with Hashimoto thyroiditis.

Endocr Res 2016 Aug 9;41(3):218-22. Epub 2016 May 9.

a Department of Nuclear Medicine , Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , People's Republic of China.

Purpose: This study was designed to investigate the clinical value of serum thyroglobulin (Tg) and antithyroglobulin antibody (TgAb) measurements and the cutoff value after ablation in differentiated thyroid carcinoma (DTC) complicated by Hashimoto thyroiditis (HT) with metastasis.

Materials And Methods: We measured serum Tg and TgAb levels and evaluated the disease status in 164 cases of DTC coexistent with HT in pathologically confirmed patients after surgery and post-remnant ablation during a 3-year follow-up. All Tg and TgAb levels were assessed by chemiluminescent immunoassay (IMA). Receiver operating characteristic (ROC) curve analysis was used to evaluate the prognostic value of Tg and TgAb for disease metastasis. The relationship between Tg and TgAb was analyzed using the scatter diagram distribution method.

Results: We found that the cutoff values of Tg and TgAb were 1.48 µg/L and 45 kIU/L, respectively. The area under the ROC curve (AUC) of Tg and TgAb was 0.907 and 0.650, respectively.

Conclusions: In DTC coexistent with HT patients, the optimal cutoff value correlated with metastasis in Tg and TgAb was 1.48 µg/L and 45 kIU/L, respectively.
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http://dx.doi.org/10.3109/07435800.2015.1010210DOI Listing
August 2016

Renal myopericytoma: case report and review of literature.

Arch Pathol Lab Med 2012 May;136(5):563-6

Department of Pathology and Laboratory Medicine, The University of Texas Medical School at Houston, 6431 Fannin St, Houston TX 77030, USA.

Myopericytoma arising in the visceral organs is rare and only 1 case of renal myopericytoma has been reported in the literature to date. We report the second case of myopericytoma arising in the kidney in a 40-year-old Hispanic woman who presented with pain on the left side of the abdomen and frequent urination. Abdominal computed tomography scan showed an exophytic left-sided renal mass. Partial nephrectomy was performed. The patient remains free of disease at 24 months after diagnosis. Our case is histologically distinct from the previously described case as it lacks the "hemangiopericytic/glomangiopericytoma" pattern. The tumor in our case showed the characteristic pattern of myopericytoma and an additional glomus tumorlike pattern. The tumor cells showed diffuse reactivity for vimentin, smooth muscle actin, smooth muscle myosin heavy chain, and muscle-specific actin in both morphologic patterns and strong diffuse CD34 expression in glomus tumorlike focus. This case report adds to the morphologic heterogeneity of myopericytomas.
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http://dx.doi.org/10.5858/arpa.2011-0387-CRDOI Listing
May 2012

Lysophosphatidic acid causes endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells.

Atherosclerosis 2012 May 13;222(1):74-83. Epub 2012 Feb 13.

Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

Aim: The objective of this study was to determine the effects of lysophosphatidic acid (LPA) on endothelial functions and molecular alternations in both porcine coronary arteries and human coronary artery endothelial cells (HCAECs).

Methods And Results: The vessel rings and HCAECs were treated with clinically relevant concentrations of LPA for different times. Vasomotor reactivity was studied with a myograph tension system. LPA (10 and 50 μM) treatment for the vessel rings significantly reduced endothelium-dependent vasorelaxation in response to bradykinin (×10(-5)M) by 32% and 49%, respectively, compared with the control (P<0.05). LPA decreased endothelial nitric oxide synthase (eNOS) mRNA and immunoreactivity levels in the vessel rings. In HCAECs, LPA reduced eNOS mRNA, phospho-eNOS and total eNOS protein levels. In addition, superoxide anion levels in LPA-treated vessel rings and HCAECs were significantly increased by lucegenin-enhanced chemiluminescence assay and dihydroethidium staining, respectively. Mitochondrial membrane potential and ATP content in LPA-treated HCAECs were substantially decreased. The mRNA levels of reactive oxygen species generating enzymes NOX4 and p40(phox) were increased, while endogenous antioxidant enzyme superoxide dismutase 1 was decreased in response to LPA treatment in HCAECs. Furthermore, exogenous antioxidant molecule selenomethionine (SeMet) effectively reversed these LPA-induced effects in both porcine coronary arteries and HCAECs.

Conclusions: LPA causes endothelial dysfunction by a mechanism associated with decreased eNOS expression and increased oxidative stress in porcine coronary arteries and HCAECs.
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http://dx.doi.org/10.1016/j.atherosclerosis.2012.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334473PMC
May 2012

2,6-Dibromo-4-(2-hy-droxy-eth-yl)phenol.

Acta Crystallogr Sect E Struct Rep Online 2011 Dec 12;67(Pt 12):o3263-4. Epub 2011 Nov 12.

The title compound, C(8)H(8)Br(2)O(2), crystallized with two independent mol-ecules (A and B) in the asymmetric unit. They differ in the conformation of the 2-hy-droxy-ethyl chain with the C-C-C-O torsion angle being -68.0 (12)° in mol-ecule A and 172.2 (9)° in mol-ecule B. In the crystal, the A mol-ecules are linked via pairs of O-H⋯O hydrogen bonds, forming inversion dimers, while the B mol-ecules are linked via an O-H⋯O hydrogen bond, forming a polymeric chain propagating in [010]. In addition, there are O-H⋯O and O-H⋯Br hydrogen bonds, and Br⋯Br [3.599 (2) Å] and π-π inter-actions [centroid-centroid distances = 3.581 (6) and 3.931 (6) Å], leading to the formation of a two-dimensional network parallel to (001).
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http://dx.doi.org/10.1107/S1600536811046538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238923PMC
December 2011

Remifentanil-induced pronociceptive effect and its prevention with pregabalin.

Korean J Anesthesiol 2011 Mar 30;60(3):198-204. Epub 2011 Mar 30.

Department of Anesthesiology and Pain Medicine, Myongji Hospital, Kwandong University Medical School, Goyang, Korea.

Background: Experimental and clinical studies have suggested that remifentanil probably causes acute tolerance or postinfusion hyperalgesia. This study was designed to confirm whether remifentanil given during propofol anesthesia induced postoperative pain sensitization, and we wanted to investigate whether pregabalin could prevent this pronociceptive effect.

Methods: Sixty patients who were scheduled for total abdominal hysterectomy were randomly allocated to receive (1) a placebo as premedication and an intraoperative saline infusion (control group), (2) a placebo as premedication and an intraoperative infusion of remifentanil at a rate of 3-4 ng/ml (remifentanil group), or (3) pregabalin 150 mg as premedication and an intraoperative infusion of remifentanil at a rate of 3-4 ng/ml (pregabalin-remifentanil group). Postoperative pain was controlled by titration of fentanyl in the postanesthetic care unit (PACU), followed by patient-controlled analgesia (PCA) with fentanyl. The patients were evaluated using the visual analogue scale (VAS) for pain scores at rest and after cough, consumption of fentanyl, sedation score and any side effects that were noted over the 48 h postoperative period.

Results: The fentanyl titration dose given in the PACU was significantly larger in the remifentanil group as compared with those of the other two groups. At rest, the VAS pain score in the remifentanil group at 2 h after arrival in the PACU was significantly higher than those in the other two groups.

Conclusions: The results of this study show that remifentanil added to propofol anesthesia causes pain sensitization in the immediate postoperative period. Pretreatment with pregabalin prevents this pronociceptive effect and so this may be useful for the management of acute postoperative pain when remifentanil and propofol are used as anesthetics.
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http://dx.doi.org/10.4097/kjae.2011.60.3.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071484PMC
March 2011

Matrix metalloproteinases modulated by protein kinase Cε mediate resistin-induced migration of human coronary artery smooth muscle cells.

J Vasc Surg 2011 Apr 31;53(4):1044-51. Epub 2011 Jan 31.

Division of Vascular and Endovascular Surgery, Department of Surgery, Stanford University, Stanford, CA 94304, USA.

Background: Emerging evidence showed that resistin induces vascular smooth muscle cell (VSMC) migration, a critical step in initiating vascular restenosis. Adhesion molecule expression and cytoskeletal rearrangement have been observed in this progress. Given that matrix metalloproteinases (MMPs) also regulate cell migration, we hypothesized that MMPs may mediate resistin-induced VSMC migration.

Methods: Human VSMCs were treated with recombinant human resistin at physiologic (10 ng/mL) and pathologic (40 ng/mL) concentrations for 24 hours. Cell migration was determined by the Boyden chamber assay. MMP and tissue inhibitor metalloproteinase (TIMP) mRNA and protein levels were measured with real-time PCR and ELISA. MMP enzymatic activity was measured by zymography. In another experiment, neutralizing antibodies against MMP-2 and MMP-9 were coincubated with resistin in cultured VSMCs. The regulation of MMP by protein kinase C (PKC) was determined by εV1-2, a selective PKCε inhibitor.

Results: Resistin-induced smooth muscle cell (SMC) migration was confirmed by the Boyden chamber assay. Forty nanograms/milliliter resistin increased SMC migration by 3.7 fold. Additionally, resistin stimulated MMP-2 and -MMP9 mRNA and protein expressions. In contrast, the TIMP-1 and TIMP-2 mRNA levels were inhibited by resistin. Neutralizing antibodies against MMP-2 and MMP-9 effectively reversed VSMC migration. Furthermore, resistin activated PKCε, but selective PKCε inhibitor suppressed resistin-induced MMP expression, activity, and cell migration.

Conclusions: Our study confirmed that resistin increased vascular smooth muscle cell migration in vitro. In terms of mechanism, resistin-stimulated cell migration was associated with increased MMP expression, which was dependent on PKCε activation.
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http://dx.doi.org/10.1016/j.jvs.2010.10.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538810PMC
April 2011

Therapeutic potential for protein kinase C inhibitor in vascular restenosis.

J Cardiovasc Pharmacol Ther 2011 Jun 23;16(2):160-7. Epub 2010 Dec 23.

Division of Vascular and Endovascular Surgery, Department of Surgery, Stanford University, Stanford, CA 94350, USA.

Vascular restenosis, an overreaction of biological response to injury, is initialized by thrombosis and inflammation. This response is characterized by increased smooth muscle cell migration and proliferation. Available pharmacological treatments include anticoagulants, antiplatelet agents, immunosuppressants, and antiproliferation agents. Protein kinase C (PKC), a large family of serine/threonine kinases, has been shown to participate in various pathological stages of restenosis. Consequently, PKC inhibitors are expected to exert a wide range of pharmacological activities therapeutically beneficial for restenosis. In this review, the roles of PKC isozymes in platelets, leukocytes, endothelial cells, and smooth muscle cells are discussed, with emphasis given to smooth muscle cells. We will describe cellular and animal studies assessing prevention of restenosis with PKC inhibitors, particularly targeting -α, -β, -δ, and -ζ isozymes. The delivery strategy, efficacy, and safety of such PKC regulators will also be discussed.
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http://dx.doi.org/10.1177/1074248410382106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527091PMC
June 2011

Distribution of inflammatory mediators in carotid and femoral plaques.

J Am Coll Surg 2010 Jul;211(1):92-8

Division of Vascular and Endovascular Surgery, Department of Surgery, Stanford University, Stanford, CA 94305, USA.

Background: Although atherosclerosis is a known systemic process, carotid and femoral atherosclerotic plaques are associated with distinctive complications and therapeutic outcomes. The purpose of this study was to evaluate inflammatory markers associated with carotid and femoral plaques.

Study Design: Carotid and femoral endarterectomy specimens were harvested from surgical patients. The carotid specimens were further sectioned into central, peripheral, and relatively normal regions. Expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in carotid and femoral specimens were compared and the distributions of MMP-2, MMP-9, and CD40 within the carotid specimens were further analyzed. Messenger RNA (mRNA) levels were measured with real-time polymerase chain reaction and proteins with ELISA assay and Western blot.

Results: Despite no significant difference in the MMP-2 mRNA levels between carotid and femoral specimens, the common femoral specimens had significantly lower MMP-2 protein production and higher MMP-9 mRNA and protein expressions than those of the carotid specimens (p = 0.015, p = 0.03, and p = 0.034, respectively). Among carotid specimens, MMP-2 mRNA level was significantly lower in the central region (p < 0.01) and consistent with the distribution pattern of MMP-2 proteins. Interestingly, despite significantly lower MMP-9 mRNA expression in the central region of carotid plaques, active MMP-9 protein level was significantly higher. CD40 mRNA and protein levels were also higher in the central region. Immunohistochemistry analyses showed substantially increased macrophages and CD40 in the central region of the carotid plaques.

Conclusions: This study emphasizes that femoral and carotid plaques are distinct entities and that distribution of inflammatory molecular markers varied within these advanced atherosclerotic plaques. Additional analyses are warranted.
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http://dx.doi.org/10.1016/j.jamcollsurg.2010.02.054DOI Listing
July 2010

Sorafenib downregulates ERK/Akt and STAT3 survival pathways and induces apoptosis in a human neuroblastoma cell line.

Int J Clin Exp Pathol 2010 Apr 23;3(4):408-15. Epub 2010 Apr 23.

Department of Pathology and Laboratory Medicine, University of Texas Health Science Center-Medical School at Houston, MSB 2.286, Houston, TX 77030, USA.

Neuroblastoma is a common solid tumor in children and its tumorigenicity is enhanced by the expression of survival pathways such as Akt and signal transducer and activator of transcription 3 (STAT3). Sorafenib is a multikinase inhibitor that also inhibits STAT3 signaling and induces apoptosis. In this study, we will examine the efficacy of sorafenib on a human neuroblastoma cell line (SK-N-AS) and also investigate its possible mechanisms. After cells reached 50-60% confluence, they were treated with various concentrations of sorafenib (0, 0.1, 1, 5, 10 and 20 microM) for different periods of time. The cell viability and apoptosis were determined by MTS colorimetric assay and TUNEL, respectively. Phosphorylation of Akt1/2/3 (p-Akt1/2/3), extracellular signal-regulated kinase 1/2 (p-ERK1/2), STAT3 (p-STAT3), and AMP-activated protein kinase alpha subunit (p-AMPKalpha) were determined with Western blot. The results indicate that as early as 2 hours post-treatment, cell viability was significantly decreased at 10 microM concentration. In 24 hours or longer treatment groups, sorafenib at 5 microM and above significantly decreased cell viability. TUNEL assay showed a significant increased of apoptosis in 5 and 20 microM treatment groups 24 hours after treatment. Western blots showed a decrease of p-ERK1/2, p-Akt1/2/3, p-STAT3, and p-AMPKalpha expression levels in various sorafenib treatment groups. Our results indicate that sorafenib significantly decreased cell viability and increased apoptosis in human neuroblastoma cell line in association with down-regulation of p-ERK1/2, p-Akt, p-STAT3 survival pathways. These data suggested potential clinical application of sorafenib in the treatment of neuroblastoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872747PMC
April 2010

Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells.

Am J Physiol Heart Circ Physiol 2010 Jul 30;299(1):H193-201. Epub 2010 Apr 30.

Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Dept. of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Resistin is a newly discovered adipocyte-derived cytokine that may play an important role in insulin resistance, diabetes, adipogenesis, inflammation, and cardiovascular disease. However, it is largely unknown whether resistin impairs endothelial functions by affecting the endothelial nitric oxide synthase (eNOS) system. In this study, we determined the effect of human recombinant resistin protein on eNOS expression and regulation in human coronary artery endothelial cells (HCAECs). When cells were treated with clinically relevant concentrations of resistin (40 or 80 ng/ml) for 24 h, the levels of eNOS mRNA, protein, and activity and eNOS mRNA stability were significantly reduced. Cellular nitric oxide levels were also decreased. In addition, the cellular levels of reactive oxygen species (ROS), including superoxide anion, were significantly increased in resistin-treated HCAECs. Mitochondrial membrane potential and the activities of catalase and superoxide dismutase were reduced. Three antioxidants, seleno-L-methionine, ginsenoside Rb1, and MnTBAP (superoxide dismutase mimetic), effectively blocked resistin-induced eNOS downregulation. Meanwhile, resistin activated the mitogen-activated protein kinases p38 and c-Jun NH(2)-terminal kinase (JNK), and the specific p38 inhibitor SB-239063 effectively blocked resistin-induced ROS production and eNOS downregulation. Furthermore, immunoreactivity of resistin was increased in atherosclerotic regions of human aorta and carotid arteries. Thus resistin directly induces eNOS downregulation through overproduction of ROS and activation of p38 and JNK in HCAECs. Resistin-induced mitochondrial dysfunction and imbalance in cellular redox enzymes may be the underlying mechanisms of oxidative stress.
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http://dx.doi.org/10.1152/ajpheart.00431.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904138PMC
July 2010

In vivo assessment of the effects of ginsenoside Rb1 on intimal hyperplasia in ApoE knockout mice.

J Surg Res 2010 Jul 11;162(1):26-32. Epub 2010 Feb 11.

Department of Surgery, Division of Vascular and Endovascular Surgery, Stanford University, Stanford, California 94025, USA.

Objective: This study investigated the effects of ginsenoside Rb1 (Rb1) on injury-induced intimal hyperplasia in ApoE knock out (ApoE -/-) mice. We also examined the value of an ultrasound micro-image system in dynamic monitoring of lumen diameter and flow velocity.

Methods: After guide wire injury of the distal left common carotid artery (CCA), ApoE-/- mice were treated with intraperitoneal infusion of normal saline (NS), homocysteine (Hcy), ginsenoside Rb1 (Rb1), or Hcy+Rb1 for 4 wk. Bilateral CCA luminal diameters and flow velocities were measured with an ultrasound micro-image system before surgery and weekly afterwards. Following the final ultrasound, CCAs were harvested and analyzed for intima-medium thickness ratios.

Results: Progressive reduction in luminal diameters and increase in flow velocity of the injured left distal CCA segment were observed using ultrasound micro-imaging system in all groups compared with the relatively stable left proximal CCA and right CCA. The NS and Hcy groups had significantly higher degree of diameter reduction compared with the Rb1 and Rb1+Hcy groups. The ultrasound findings were consistent with histology analyses at 4 wk post-op.

Conclusions: The study suggested that Rb1 attenuated the effects of Hcy on injured carotid arteries of ApoE -/- mice. The study also showed that ultrasound micro-image system was a reliable tool in monitoring luminal reduction after injury in a murine model. This study establishes a fundamental step of in vivo monitoring of the therapeutic effects of agents in a murine model without sacrificing the animals.
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http://dx.doi.org/10.1016/j.jss.2010.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885510PMC
July 2010

[Prognostic impact of heart block during transcatheter closure of ventricular septal defect].

Zhonghua Xin Xue Guan Bing Za Zhi 2009 Nov;37(11):990-3

Department of Cardiology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.

Objective: To investigate the prognostic impact of heart block during the transcatheter closure of ventricular septal defect (VSD).

Methods: Forty three patients developed complete left or right bundle branch block (CLBBB, CRBBB), incomplete left or right bundle branch block (ILBBB, IRBBB), and atrioventricular block (AVB) during and within 1 week post procedure were followuped at 1, 6, 12, 24, 36, 48 and 60 months post procedure. Electrocardiogram, dynamic electrocardiogram and transthoracic echocardiography were made.

Results: Bundle branch block and atrioventricular block were detected in 26 patients (CLBBB n = 4, CRBBB n = 5, ILBBB n = 2, IRBBB n = 10 and third-degree AVB n = 5) during the transcatheter closure of VSD, and in 17 patients (CLBBB n = 5, CRBBB n = 2, first-degree AVB n = 3, second-degree I-type AVB n = 1 and third-degree AVB n = 6) within 1 week post procedure. Heart block disappeared in 33 patients (76.7%) before discharge, in 37 patients (86.1%) at 1 month and in 41 patients (95.4%) at 6 months post procedure. CLBBB or CRBBB was seen in two cases at 24 months after closure. There was no heart failure and serious cardiac dilatation during follow up.

Conclusion: The heart block occurred during the periprocedure period of transcatheter closure of VSD was a benign phenomenon without prognostic importance.
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November 2009

Field effect in cancer-an update.

Ann Clin Lab Sci 2009 ;39(4):331-7

Department of Pathology and Laboratory Medicine, University of Texas Medical School-Houston, Houston, Texas 77030, USA.

The concept "field effect in cancer" originated in 1953 from the histopathological observations of Slaughter and colleagues [1] regarding the occurrence of multiple primary oral squamous cell carcinomas and their local recurrences. The development of modern molecular technologies has extended the field effect concept by exploring the molecular abnormalities in tissues that appear histologically normal. To date, such field effect biomarkers have been reported in several sites and organs, eg, head and neck, colon and rectum, prostate, breast, lung, esophagus, stomach, and skin. Two popular hypotheses have been proposed. One hypothesis implicates genetic alterations that occur in a stepwise fashion (initiation, promotion, and progression); a clone gains growth advantage and acquires more genetic alterations, which eventually result in cancer. A second hypothesis focuses on epigenetic alterations, which include hypermethylation of the DNA promoter of certain tumor suppressor genes, leading to down-regulation of these genes. In this update, we discuss in detail the evidence that supports these two hypotheses. In addition, we attempt to provide a comprehensive overview of the field effect in carcinogenesis and its possible mechanisms in various organs. Moreover, we discuss the potential utilization of field effect biomarkers in cancer prevention, surgical considerations, and clinical prognosis.
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September 2013

Lactosylceramide causes endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells.

Med Sci Monit 2009 Sep;15(9):BR270-4

Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

Background: Lactosylceramide (LacCer) is a member of the glycosphingolipid family, which has been implicated in the atherogenic process. The goal of this study was to determine the effects and molecular mechanisms of LacCer on endothelial functions in porcine coronary arteries and human coronary endothelial cells (HCAECs).

Material/methods: The vessel rings and HCAECs were treated with different concentrations of LacCer for 24 hours. Vasomotor function was studied using a myograph tension system in response to thromboxane A2 analog U46619, bradykinin and sodium nitroprusside (SNP). Superoxide anion production was determined using lucigenin-enhanced chemiluminescence. The expression of endothelial nitric oxide synthase (eNOS), NADPH oxidase subunit NOX4 and catalase was determined by real-time PCR.

Results: LacCer (0.1, 1 and 10 microM) significantly decreased endothelium-dependent vasorelaxation (bradykinin) in porcine coronary artery rings in a concentration-dependent manner compared with untreated controls (P<0.05). High concentration of LacCer (10 microM) also reduced endothelium-independent vasorelaxation (SNP). However, LacCer did not affect vessel contraction (U46619). Antioxidant selenomethionine (SeMet) effectively reversed LacCer-induced endothelial dysfunction in the vessel rings. Furthermore, LacCer significantly increased superoxide anion production in the vessel rings in a concentration-dependent manner compared with untreated controls (P<0.05). In response to LacCer treatment, NOX4 mRNA levels were significantly increased, while the expression of catalase and eNOS was significantly decreased in HCAECs compared with controls (P<0.05).

Conclusions: LacCer causes endothelial dysfunction with potential mechanisms of the down-regulation of eNOS and increase of oxidative stress due to the activation of NADPH oxidase and inhibition of internal antioxidant catalase. This study suggests that LacCer may represent a risk factor to the vascular system and antioxidant SeMet may have clinical applications for prevention of vascular disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927961PMC
September 2009

Soluble CD40 ligand induces human coronary artery smooth muscle cells proliferation and migration.

Surgery 2009 Jul 30;146(1):5-11. Epub 2009 May 30.

Division of Vascular and Endovascular Surgery, Department of Surgery, Stanford University, Stanford, Palo Alto, CA 94305, USA.

Background: Clinical data have shown that an increased level of serum soluble CD40 ligand (sCD40L) is associated with atherosclerogenesis. We hypothesize that sCD40L induces proliferation and migration of vascular smooth muscle cells (VSMCs) through activation of matrix metalloproteinases (MMPs).

Methods: Human VSMCs were treated with sCD40L (1 or 5 microg/mL). Cell proliferation and migration were studied using a nonradioactive cell proliferation assay (MTT) and a modified Boyden chamber combined with a scrape-wound assay, respectively. Messenger RNA (mRNA) and protein levels of MMP-2 and MMP-9 were measured with real-time polymerase chain reaction and enzyme-linked immunosorbent assays. Neutralizing antibodies against MMP-2 or MMP-9 were used to evaluate their effects on sCD40L-induced cell proliferation and migration.

Results: MTT assay showed a 35% increase in cell proliferation in the high-dose (5 microg/mL) sCD40L-treated group. Cell migration was also increased by 33% (Transwell assay) to 3-fold (scrape-wound assay) after high-dose sCD40L treatment. When cells were treated with 5 microg/mL of sCD40L for 24 hours, significant decreases in MMP-2 and increases in MMP-9 mRNA and protein levels were observed. Neutralizing antibodies against MMP-9 effectively blocked sCD40L-induced cell proliferation and migration.

Conclusion: This study suggests that sCD40L increases VSMC proliferation and migration through the MMP-9 pathway, which may be a potential mechanism through which sCD40L induces intimal hyperplasia and atherosclerosis.
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http://dx.doi.org/10.1016/j.surg.2009.04.004DOI Listing
July 2009

Chlamydia heat shock protein 60 decreases expression of endothelial nitric oxide synthase in human and porcine coronary artery endothelial cells.

Cardiovasc Res 2009 Sep 14;83(4):768-77. Epub 2009 May 14.

Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Molecular Surgeon Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Aims: Clinically, Chlamydia pneumoniae infection and its heat shock protein 60 (cHSP60) may contribute to atherogenesis; however, its underlying mechanisms are largely unknown. The objective of this study was to determine whether cHSP60 could cause endothelial dysfunction in human coronary artery endothelial cells (HCAECs) and porcine coronary arteries.

Methods And Results: When HCAECs were treated with recombinant cHSP60, endothelial nitric oxide synthase (eNOS) mRNA and protein levels, enzyme activities, cellular NO levels, mRNA stability, and promoter activities were significantly decreased. Superoxide anion production was significantly increased due to the inhibition of mitochondrial membrane potential and catalase and superoxide dismutase (SOD) activities as well as activation of NADPH oxidase. Antioxidant seleno-l-methionine (SeMet) or SOD mimetic MnTBAP effectively blocked cHSP60-induced eNOS downregulation. In addition, cHSP60 activated mitogen-activated protein kinases (MAPKs) including p38, c-Jun-N-terminal kinase/stress-activated protein kinase, and extracellular signal-regulated kinases. Specific chemical inhibitors or their dominant-negative mutant forms of these MAPKs effectively blocked cHSP60-induced eNOS downregulation. cHSP60-induced eNOS downregulation and oxidative stress were also demonstrated in porcine coronary artery rings in vitro. Functionally, endothelium-dependent vasorelaxation was significantly reduced in cHSP60-treated vessels.

Conclusion: cHSP60 directly induces eNOS downregulation through oxidative stress and MAPK activation in both HCAECs and porcine coronary arteries, thereby causing endothelial dysfunction.
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http://dx.doi.org/10.1093/cvr/cvp150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725775PMC
September 2009

Roles and mechanisms of human immunodeficiency virus protease inhibitor ritonavir and other anti-human immunodeficiency virus drugs in endothelial dysfunction of porcine pulmonary arteries and human pulmonary artery endothelial cells.

Am J Pathol 2009 Mar 13;174(3):771-81. Epub 2009 Feb 13.

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM390, Houston, TX 77030, USA.

The objective of this study was to determine the effects of highly active antiretroviral therapy (HAART) drugs on pulmonary endothelial function. Porcine pulmonary arteries or human pulmonary arterial endothelial cells (HPAECs) were incubated with eight HAART drugs [ritonavir, indinavir, lopinavir, zidovudine (AZT), abacavir, stavudine, didanosine (ddI), and lamivudine] individually or in combination [three HAART drugs (3-plex; indinavir, stavudine, and ddI)] at their clinical plasma concentrations for 24 hours. Endothelium-dependent vasorelaxation in response to bradykinin was reduced significantly by the ritonavir in a concentration-dependent manner. Five other HAART drugs (indinavir, lamivudine, abacavir, AZT, and ddI) and the 3-plex significantly also impaired endothelium-dependent vasorelaxation in response to bradykinin. Five HAART drugs (ritonavir, indinavir, lamivudine, abacavir, and AZT) significantly decreased endothelial nitric oxide synthase (eNOS) expression and increased superoxide anion levels in both vessels and HPAECs. Furthermore, both ritonavir and AZT substantially activated ERK2 in HPAECs. Additionally, the antioxidants ginsenoside Rb1 and ginkgolide A effectively reversed HAART drug-induced vasomotor dysfunction and eNOS down-regulation. Inhibition of ERK1/2 also partially blocked ritonavir- and AZT-induced down-regulation of eNOS and vasomotor dysfunction. Thus, HAART drugs significantly impair endothelial functions of porcine pulmonary arteries and HPAECs, which may be mediated by eNOS down-regulation, oxidative stress, and ERK1/2 activation. These findings suggest that HAART drugs may contribute to the high incidence of pulmonary artery hypertension in human immunodeficiency virus-infected patients.
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http://dx.doi.org/10.2353/ajpath.2009.080157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665739PMC
March 2009

Ginsenoside Rb1 attenuates homocysteine-augmented guidewire injury-induced intimal hyperplasia in mice.

J Surg Res 2009 Dec 15;157(2):193-8. Epub 2008 Aug 15.

Division of Vascular and Endovascular Surgery, Department of Surgery, Stanford University, Stanford, California, USA.

Background: Intimal hyperplasia (IH) is the primary cause for post-angioplasty restenosis. The purpose of this study is to investigate the effects of homocysteine (Hcy) and ginsenoside Rb1 (Rb1) on IH using a guidewire injury animal model.

Methods: In 12-wk-old C57BL/6J mice, the left common carotid artery (CCA) was denudated with a guidewire and the right CCA was used as the uninjured control. They were treated with saline (NS), Hcy, Rb1, or Hcy + Rb1 for 4 wk prior to sacrifice. Animals were sacrificed at 4, 6, or 8 wk. Both CCAs were harvested and intimal-medium thickness (IMT) ratios were calculated. Local macrophage distribution was also studied.

Results: Histology analyses demonstrated consistent internal elastic lamina disruption and focal IH in the injured CCA segments. The degree of IH correlated to the lengths of time following injury. Hcy treated group had significant increase in IMT compared with the NS group (P < 0.05), while Rb1 group was similar to the NS group. In addition, Hcy + Rb1 group showed significant improvement in IMT compared with Hcy group (P < 0.01). Furthermore, Hcy significantly increased local macrophage content as compared with either lesion alone or Rb1 treated animals.

Conclusions: Our study showed that Hcy increased the degree of IH and macrophage content in the injured CCA and that Rb1 attenuated these adverse effects. These changes might be mediated through antioxidative effects of Rb1. Our data suggests a potential clinical application of ginseng in controlling Hcy-related vascular injuries.
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http://dx.doi.org/10.1016/j.jss.2008.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066179PMC
December 2009

Growth hormone-releasing peptide ghrelin inhibits homocysteine-induced endothelial dysfunction in porcine coronary arteries and human endothelial cells.

J Vasc Surg 2009 Jan 22;49(1):199-207. Epub 2008 Nov 22.

Michael E DeBakey Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, Molecular Surgeon Research Center, Baylor College of Medicine , Houston, Texas 77030-3411, USA.

Objective: Ghrelin, a novel growth hormone-releasing peptide, is implicated to play a protective role in cardiovascular tissues. However, it is not clear whether ghrelin protects vascular tissues from injury secondary to risk factors such as homocysteine (Hcy). This study investigated the effect and potential mechanisms of ghrelin on Hcy-induced endothelial dysfunction.

Methods: Porcine coronary artery rings were incubated for 24 hours with ghrelin (100 ng/mL), Hcy (50 microM), or ghrelin plus Hcy. Endothelial vasomotor function was evaluated using the myograph tension model. The response to the thromboxane A(2)analog U46619, bradykinin, and sodium nitroprusside was analyzed. Endothelial nitric oxide synthase (eNOS) expression was determined using real-time polymerase chain reaction and immunohistochemistry staining, and superoxide anion production was documented lucigenin-enhanced chemiluminescence analysis. Human coronary artery endothelial cells (HCAECs) were treated with different concentrations of Hcy, ghrelin, or antighrelin receptor antibody for 24 hours, and eNOS protein levels were determined by Western blot analysis.

Results: Maximal contraction with U46619 and endothelium-independent vasorelaxation with sodium nitroprusside were not different among the four groups. However, endothelium-dependent vasorelaxation with bradykinin (10(-6) M) was significantly reduced by 34% with Hcy compared with controls (P < .05). The addition of ghrelin to Hcy had a protective effect, with 61.6% relaxation, which was similar to controls (64.7%). Homocysteine significantly reduced eNOS expression, whereas ghrelin cotreatment effectively restored eNOS expression to the control levels. Superoxide anion levels, which were increased by 100% with Hcy, returned to control levels with ghrelin cotreatment. Ghrelin also effectively blocked the Hcy-induced decrease of eNOS protein levels in HCAECs in a concentration-dependent manner. Antighrelin receptor antibody effectively inhibited the effect of ghrelin.

Conclusion: Ghrelin has a protective effect in the porcine coronary artery by blocking Hcy-induced endothelial dysfunction, improving eNOS expression, and reducing oxidative stress. Ghrelin also shows a protective effect on HCACEs from the Hcy-induced decrease in eNOS protein levels. The effect of ghrelin is receptor-dependent. Thus, ghrelin administration may have beneficial effects in the treatment of vascular disease in patients with hyperhomocysteinemia.
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http://dx.doi.org/10.1016/j.jvs.2008.08.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652132PMC
January 2009

Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells.

Am J Physiol Heart Circ Physiol 2008 Dec 17;295(6):H2399-408. Epub 2008 Oct 17.

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Mail stop: BCM390, Houston, TX 77030, USA.

The objective of this study was to determine the effects and mechanisms of serum amyloid A (SAA) on coronary endothelial function. Porcine coronary arteries and human coronary arterial endothelial cells (HCAECs) were treated with SAA (0, 1, 10, or 25 microg/ml). Vasomotor reactivity was studied using a myograph tension system. SAA significantly reduced endothelium-dependent vasorelaxation of porcine coronary arteries in response to bradykinin in a concentration-dependent manner. SAA significantly decreased endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein levels as well as NO bioavailability, whereas it increased ROS in both artery rings and HCAECs. In addition, the activities of internal antioxidant enzymes catalase and SOD were decreased in SAA-treated HCAECs. Bio-plex immunoassay analysis showed the activation of JNK, ERK2, and IkappaB-alpha after SAA treatment. Consequently, the antioxidants seleno-l-methionine and Mn(III) tetrakis-(4-benzoic acid)porphyrin and specific inhibitors for JNK and ERK1/2 effectively blocked the SAA-induced eNOS mRNA decrease and SAA-induced decrease in endothelium-dependent vasorelaxation in porcine coronary arteries. Thus, SAA at clinically relevant concentrations causes endothelial dysfunction in both porcine coronary arteries and HCAECs through molecular mechanisms involving eNOS downregulation, oxidative stress, and activation of JNK and ERK1/2 as well as NF-kappaB. These findings suggest that SAA may contribute to the progress of coronary artery disease.
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http://dx.doi.org/10.1152/ajpheart.00238.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614654PMC
December 2008

Soluble CD40 ligand induces endothelial dysfunction in human and porcine coronary artery endothelial cells.

Blood 2008 Oct 24;112(8):3205-16. Epub 2008 Jul 24.

Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.

The purpose of this study was to determine the effects and mechanisms of sCD40L on endothelial dysfunction in both human coronary artery endothelial cells (HCAECs) and porcine coronary artery rings. HCAECs treated with sCD40L showed significant reductions of endothelial nitric oxide synthase (eNOS) mRNA and protein levels, eNOS mRNA stability, eNOS enzyme activity, and cellular NO levels, whereas superoxide anion (O(2)(-)) production was significantly increased. sCD40L enhanced eNOS mRNA 3'UTR binding to cytoplasmic molecules and induced a unique expression pattern of 95 microRNAs. sCD40L significantly decreased mitochondrial membrane potential, and catalase and SOD activities, whereas it increased NADPH oxidase (NOX) activity. sCD40L increased phosphorylation of MAPKs p38 and ERK1/2 as well as IkappaBalpha and enhanced NF-kappaB nuclear translocation. In porcine coronary arteries, sCD40L significantly decreased endothelium-dependent vasorelaxation and eNOS mRNA levels, whereas it increased O(2)(-) levels. Antioxidant seleno-l-methionine; chemical inhibitors of p38, ERK1/2, and mitochondrial complex II; as well as dominant negative mutant forms of IkappaBalpha and NOX4 effectively blocked sCD40L-induced eNOS down-regulation in HCAECs. Thus, sCD40L reduces eNOS levels, whereas it increases oxidative stress through the unique molecular mechanisms involving eNOS mRNA stability, 3'UTR-binding molecules, microRNAs, mitochondrial function, ROS-related enzymes, p38, ERK1/2, and NF-kappaB signal pathways in endothelial cells.
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http://dx.doi.org/10.1182/blood-2008-03-143479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569174PMC
October 2008

Growth-related oncogene-alpha induces endothelial dysfunction through oxidative stress and downregulation of eNOS in porcine coronary arteries.

Am J Physiol Heart Circ Physiol 2007 Nov 14;293(5):H3088-95. Epub 2007 Sep 14.

Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

Growth-related oncogene-alpha (GRO-alpha) is a member of the CXC chemokine family, which is involved in the inflammatory process including atherosclerosis. We hypothesized that GRO-alpha may affect endothelial functions in both porcine coronary arteries and human coronary artery endothelial cells (HCAECs). Vasomotor function was analyzed in response to thromboxane A2 analog U-46619 for contraction, bradykinin for endothelium-dependent vasorelaxation, and sodium nitroprusside (SNP) for endothelium-independent vasorelaxation. In response to 10(-6) M bradykinin, GRO-alpha (50 and 100 ng/ml) significantly reduced endothelium-dependent vasorelaxation by 34.73 and 48.8%, respectively, compared with controls (P < 0.05). There were no changes in response to U-46619 or SNP between treated and control groups. With the lucigenin-enhanced chemiluminescence assay, superoxide anion production in GRO-alpha-treated vessels (50 and 100 ng/ml) was significantly increased by 50 and 86%, respectively, compared with controls (P < 0.05). With real-time PCR analysis, endothelial nitric oxide synthase (eNOS) mRNA levels in porcine coronary arteries and HCAECs after GRO-alpha treatment were significantly decreased compared with controls (P < 0.05). The eNOS protein levels by both immunohistochemistry and Western blot analyses were also decreased in GRO-alpha-treated vessels. Antioxidant seleno-l-methionine and anti-GRO-alpha antibody effectively blocked these effects of GRO-alpha on both porcine coronary arteries and HCAECs. In addition, GRO-alpha immunoreactivity was substantially increased in the atherosclerotic regions compared with nonatherosclerotic regions in human coronary arteries. Thus GRO-alpha impairs endothelium-dependent vasorelaxation in porcine coronary arteries through a mechanism of overproduction of superoxide anion and downregulation of eNOS. GRO-alpha may contribute to human coronary artery disease.
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http://dx.doi.org/10.1152/ajpheart.00473.2007DOI Listing
November 2007
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