Tuesday, August 16, 2016

Differential ERK1/2 Signaling and Hypertrophic Response to Endothelin-1 in Cardiomyocytes from SHR and Wistar-Kyoto Rats: A Potential Target for Combination Therapy of Hypertension

Author(s):

Li-an Zhu, Ning-yuan Fang, Ping-jin Gao, Xian Jin, Hai-ya Wang and Zhenguo LiuPages 467-474 (8)

Abstract:


Extracellular signal regulated kinase½ (ERK1/2) signaling is critical to endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. This study was to investigate ERK1/2 signaling and hypertrophic response to ET-1 stimulation in cardiomyocytes (CMs) from spontaneous hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Primary neonatal SHR and WKY CMs were exposed to ET-1 for up to 24 hrs. Minimal basal ERK1/2 phosphorylation was present in WKY CMs, while a significant baseline ERK1/2 phosphorylation was observed in SHR CMs. ET-1 induced a time- and dose-dependent increase in ERK1/2 phosphorylation in both SHR and WKY CMs. However, ET-1-induced ERK1/2 activation occurred much earlier with significantly higher peak phosphorylation level, and stayed elevated for longer duration in SHR CMs than that in WKY CMs. ET-1-induced hypertrophic response was more prominent in SHR CMs than that in WKY CMs as reflected by increased cell surface area, intracellular actin density, and protein synthesis. Pre-treatment with ERK1/2 phosphorylation inhibitor PD98059 completely prevented ET-1-induced ERK1/2 phosphorylation and increases in cell surface area and protein synthesis in SHR and WKY CMs. The specific PI3 kinase inhibitor LY294002 blocked ET-1-induced Akt and ERK1/2 phosphorylation, and protein synthesis in CMs. These data indicated that ERK1/2 signaling was differentially enhanced in CMs, and was associated with increased cardiac hypertrophic response to ET-1 in SHR. ET-1-induced ERK1/2 activation and cardiac hypertrophy appeared to be mediated via PI3 kinase/Akt signaling in SHR and WKY. The differential ERK1/2 activation in SHR CMs by ET-1 might represent a potential target for combination therapy of hypertension.

Keywords:

Akt, cardiomyocyte hypertrophy, endothelin, ERK1/2, hypertension, spontaneous hypertensive rat.

Affiliation:

Department of Geriatrics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Shan-Dong Middle Road, Shanghai 200001, China., Davis Heart & Lung Research Institute, the Ohio State University Medical Center, DHLRI Suite 200; 473 West 12th Ave, Columbus, OH 43210, USA.


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Identification and Treatment of Patients with Homozygous Familial Hypercholesterolaemia: Information and Recommendations from a Middle East Advisory Panel

Author(s):

Abdullah Al-Ashwal, Fahad Alnouri, Hani Sabbour, Abdulraof Al-Mahfouz, Nasreen Al-Sayed, Maryam Razzaghy-Azar, Faisal Al-Allaf, Khalid Al-Waili, Yajnavalka Banerjee, Jacques Genest, Raul D. Santos and Khalid Al-RasadiPages 759-770 (12)

Abstract:


We present clinical practice guidelines for the diagnosis and treatment of homozygous familial hypercholesterolaemia (HoFH) in the Middle East region. While guidelines are broadly applicable in Europe, in the Middle East we experience a range of confounding factors that complicate disease management to a point whereby the European guidance cannot be applied without significant modification. Specifically, for disease prevalence, the Middle East region has an established epidemic of diabetes and metabolic syndrome that can complicate treatment and mask a clinical diagnosis of HoFH. We have also a high incidence of consanguineous marriages, which increase the risk of transmission of recessive and homozygous genetic disorders. This risk is further augmented in autosomal dominant disorders such as familial hypercholesterolaemia (FH), in which a range of defective genes can be transmitted, all of which contribute to the phenotypic expression of the disease. In terms of treatment, we do not have access to lipoprotein apheresis on the same scale as in Europe, and there remains a significant reliance on statins, ezetimibe and the older plasma exchange methods. Additionally, we do not have widespread access to anti-apolipoprotein B therapies and microsomal transfer protein inhibitors. In order to adapt existing global guidance documents on HoFH to the Middle East region, we convened a panel of experts from Oman, Saudi Arabia, UAE, Iran and Bahrain to draft a regional guidance document for HoFH. We also included selected experts from outside the region. This panel statement will form the foundation of a detailed appraisal of the current FH management in the Middle Eastern population and thereby provide a suitable set of guidelines tailored for the region.

Keywords:

Homozygous familial hypercholesterolaemia, prevalence, diagnosis, treatment, genetics.

Affiliation:

Department of Clinical Biochemistry, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.


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miR-135a Suppresses Calcification in Senescent VSMCs by Regulating KLF4/STAT3 Pathway

Author(s):

Lin Lin, Yue He, Bei-Li Xi, Hong-Chao Zheng, Qian Chen, Jun Li, Ying Hu, Ming-Hao Ye, Ping Chen and Yi QuPages 211-218 (8)

Abstract:


Cellular function phenotype is regulated by various microRNAs (miRs), including miR-135a. However, how miR-135a is involved in the calcification in senescent vascular smooth muscle cells (VSMCs) is not clear yet. In the present study, we first identified the significantly altered miRNAs in VSMCs, then performed consecutive passage culture of VSMCs and analyzed the expression of miR- 135a and calcification genes in the senescent phase. Next, the effects of the miR-135a inhibition on calcification and calcification genes were analyzed. The luciferase assay was used to validate the target protein of miR-135a. The western blotting was used to determine the effects of miR-135a on Krüppel-like factor 4 (KLF4) and signal transducer and activator of transcription 3 protein (STAT3) expression, as well as the relationship between KLF4 and STAT3. Finally, the quantified cellular calcification was measured to examine the involvement of miR-135a, KLF4 and STAT3 in VSMCs calcification. Our results showed that miR-135a was significantly altered in VSMCs. Cell calcification and calcification genes were greatly altered by miR-135a inhibition. KLF4 was validated as the target RNA of miR-135a. Expression of KLF4 and STAT3 were both significantly decreased by over expressed miR-135a, while the inhibition of miR-135a and KLF4 siRNA both decreased the STAT3 protein levels. Moreover, the inhibition of miR-135a dramatically increased the calcium concentration, but co-treatment with KLF4 or STAT3 siRNA both decreased the calcium concentration. The present study identified miR-135a as a potential osteogenic differentiation suppressor in senescent VSMCs and revealed that KLF4/STAT3 pathway, at least partially, was involved in the mechanism.

Keywords:

Vascular smooth muscle cell, miR-135a, calcification, KLF4, STAT3.

Affiliation:

Department of Geriatrics, Xuhui Central hospital, Shanghai Clinical Center, Chinese Academy of Science, No.966 Middle Huaihai Road, Shanghai, 200031, China.

Graphical Abstract:



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Venous Thromboembolism Risk and Adequacy of Prophylaxis in High Risk Pregnancy in the Arabian Gulf

Author(s):

Faisal Alsayegh, Waleed Al-Jassar, Salima Wani, Muna Tahlak, Awatef Albahar, Lamya Al Kharusi, Halima Al-Tamimi, Faten El-Taher, Naeema Mahmood and Ibrahim Al-ZakwaniPages 368-373 (6)

Abstract:


Objectives: To estimate the prevalence of venous thromboembolism (VTE) risk factors in pregnancy and the proportion of pregnancies at risk of VTE that received the recommended prophylaxis according to the American College of Chest Physicians (ACCP) 2012 published guidelines in antenatal clinics in the Arabian Gulf.
Methods: The evaluation of venous thromboembolism (EVE)-Risk project was a non-interventional, cross-sectional, multi-centre, multi-national study of all eligible pregnant women (≥17 years) screened during antenatal clinics from 7 centres in the Arabian Gulf countries (United Arab Emirates, Kuwait, Bahrain, Qatar and Oman). Pregnant women were recruited during a 3-month period between September and December 2012.
Results: Of 4,131 screened pregnant women, 32% (n=1,337) had ≥1 risk factors for VTE. Common VTE risk factors included obesity (76%), multiparity (33%), recurrent miscarriages (9.1%), varicose veins (6.9%), thrombophilia (2.6%), immobilization (2.0%), sickle cell disease (2.8%) and previous VTE (1.6%). Only 8.3% (n=111) of the high risk patients were on the recommended VTE prophylaxis. Enoxaparin was used in 80% (n=89) of the cases followed by tinzaparin (4%; n=4). Antiplatelet agents were prescribed in 11% (n=149) of pregnant women. Of those on anticoagulants (n=111), 59% (n=66) were also co-prescribed antiplatelet agents. Side effects (mainly local bruising at the injection site) were reported in 12% (n=13) of the cases.
Conclusion: A large proportion of pregnant women in the Arabian Gulf countries have ≥1 VTE risk factor with even a smaller fraction on prophylaxis. VTE risk assessment must be adopted to identify those at risk who would need VTE prophylaxis.

Keywords:

Venous thromboembolism, deep vein thrombosis, antiplatelet, anticoagulation, pregnancy, Middle East.

Affiliation:

Department of Pharmacology & Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos University PO Box 38, Al-Khodh, PC-123, Sultanate of Oman


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    Control of Risk Factors for Cardiovascular Disease among Multinational Patient Population in the Arabian Gulf

    Author(s):

    Ibrahim Al-Zakwani, Wael Al-Mahmeed, Mohamed Arafah, Ali T. Al-Hinai, Abdullah Shehab, Omer Al-Tamimi, Mahmoud Al-Awadhi, Shorook Al-Herz, Faisal Al-Anazi, Khalid Al-Nemer, Othman Metwally, Akram Al-Khadra, Mohammed Fakhry, Hossam Elghetany, Abdel R. Medani, Afzal H. Yusufali, Obaid Al-Jassim, Omar Al-Hallaq, Fahad O.A.S. Baslaib, Haitham Amin, Raul D. Santos, Khalid Al-Waili, Khamis Al-Hashmi and Khalid Al-RasadiPages 374-381 (8)

    Abstract:


    We evaluated the control of cardiovascular disease (CVD) risk factors among patients with atherosclerotic cardiovascular disease (ASCVD) in the Centralized Pan-Middle East Survey on the undertreatment of hypercholesterolaemia (CEPHEUS) in the Arabian Gulf. Of the 4398 enrolled patients, overall mean age was 57 ± 11 years, 60% were males, 13% were smokers, 76% had diabetes, 71% had metabolic syndrome and 78% had very high ASCVD risk status. The proportion of subjects with body mass index <25 kg/m2, HbA1c <7% (in diabetics), low-density lipoprotein cholesterol (LDL-C) <2.6 mmol/L (100 mg/dL) and <1.8 mmol/L (70 mg/dL) for high and very high ASCVD risk cohorts, respectively and controlled blood pressure (<140/90 mmHg) was 14, 26, 31% and 60%, respectively. Only 1.4% of the participants had all of their CVD risk factors controlled with significant differences among the countries (P < .001). CVD risk goal attainment rates were significantly lower in those with very high ASCVD risk compared with those with high ASCVD risk status (P < .001). Females were also, generally, less likely to attain goals when compared with males (P < .001).

    Keywords:

    Cardiovascular diseases, obesity, blood pressure, diabetes mellitus, non-HDL cholesterol, LDL cholesterol, Arabian Gulf.

    Affiliation:

    Department of Biochemistry, Sultan Qaboos University Hospital, P.O. Box 38, Al-Khod, Muscat 123, Oman.


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