Metformin prevents vascular damage in hypertension through the AMPK/ER stress pathway

Metformin is an antidiabetic drug. However, the pleiotropic beneficial effects of metformin in nondiabetic models still need to be defined. The objective of this study is to investigate the effect of metformin on angiotensin II (Ang II)-induced hypertension and cardiovascular diseases. Mice were infused with Ang II (400 ng/kg per min) with or without metformin for 2 weeks. Mice infused with angiotensin II displayed an increase in blood pressure associated with enhanced vascular endoplasmic reticulum (ER) stress markers, which were blunted after metformin treatment. Moreover, hypertension-induced reduction in phosphorylated AMPK, endothelial nitric oxide synthase (eNOs) phosphorylation, and endothelium-dependent relaxation (EDR) in mesenteric resistance arteries (MRA) were rescued after metformin treatment. Infusion of ER stress inducer (tunicamycin, Tun) in control mice induced ER stress in MRA and reduced phosphorylation of AMPK, eNOS synthase phosphorylation, and EDR in MRA without affecting systolic blood pressure (SBP). All these factors were reversed subsequently with metformin treatment. ER stress inhibition by metformin improves vascular function in hypertension. Therefore, metformin could be a potential therapy for cardiovascular diseases in hypertension independent of its effects on diabetes.ope

Vasodilatory Effect of Phellinus linteus Extract in Rat Mesenteric Arteries

Phellinus linteus is a well-known medicinal mushroom that is widely used in Asian countries. In several experimental models, Phellinus linteus extracts were reported to have various biological effects, including anti-inflammatory, anti-cancer, hepatoprotective, anti-diabetic, neuroprotective, and anti-angiogenic activity. In the present study, several bioactive compounds, including palmitic acid ethyl ester and linoleic acid, were identified in Phellinus linteus. The intermediate-conductance calcium-activated potassium channel (IKCa) plays an important role in the regulation of the vascular smooth muscle cells' (VSMCs) contraction and relaxation. The activation of the IKCa channel causes the hyperpolarization and relaxation of VSMCs. To examine whether Phellinus linteus extract causes vasodilation in the mesenteric arteries of rats, we measured the isometric tension using a wire myograph. After the arteries were pre-contracted with U46619 (a thromboxane analogue, 1 µM), Phellinus linteus extract was administered. The Phellinus linteus extract induced vasodilation in a dose-dependent manner, which was independent of the endothelium. To further investigate the mechanism, we used the non-selective K+ channel blocker tetraethylammonium (TEA). TEA significantly abolished Phellinus linteus extract-induced vasodilation. Thus, we tested three different types of K+ channel blockers: iberiotoxin (BKca channel blocker), apamin (SKca channel blocker), and charybdotoxin (IKca channel blocker). Charybdotoxin significantly inhibited Phellinus linteus extract-induced relaxation, while there was no effect from apamin and iberiotoxin. Membrane potential was measured using the voltage-sensitive dye bis-(1,3-dibutylbarbituric acid)-trimethine oxonol (DiBAC4(3)) in the primary isolated vascular smooth muscle cells (VSMCs). We found that the Phellinus linteus extract induced hyperpolarization of VSMCs, which is associated with a reduced phosphorylation level of 20 KDa myosin light chain (MLC20).ope

Natural regulatory T cells control coronary arteriolar endothelial dysfunction in hypertensive mice

Coronary artery disease in patients with hypertension is increasing worldwide and leads to severe cardiovascular complications. The cellular and molecular mechanisms that underlie this pathologic condition are not well understood. Experimental and clinical research indicates that immune cells and inflammation play a central role in the pathogenesis of cardiovascular diseases. Recently, it has been reported that CD4(+)CD25(+) regulatory T cells (Tregs) regulate heart fibrosis in hypertension. In this study, we determined the role of Tregs in coronary arteriolar endothelial dysfunction in angiotensin II-dependent hypertensive mice. Mice infused with angiotensin II had significantly increased blood pressure, as determined using telemetry, and apoptotic Treg numbers, as measured using flow cytometry. The mice displayed inflammation, assessed by macrophage activation/infiltration into coronary arterioles and the heart, and increased local tumor necrosis factor-α release, which participates in reduced coronary arteriolar endothelial-dependent relaxation in response to acetylcholine using an arteriograph. Hypertensive mice injected with Tregs isolated from control mice had significantly reduced macrophage activation and infiltration, reduced tumor necrosis factor-α release, and improved coronary arteriolar endothelium-dependent relaxation. Our novel data indicate that Tregs are important in the development of coronary arteriolar endothelial dysfunction in hypertension. These results suggest a new direction in the investigation of vascular disease in hypertension and could lead to a therapeutic strategy that involves immune system modulation using Tregs.ope

Chronic inhibition of epidermal growth factor receptor tyrosine kinase and extracellular signal-regulated kinases 1 and 2 (ERK1/2) augments vascular response to limb ischemia in type 2 diabetic mice

Type 2 diabetes is a key risk factor for ischemia-dependent pathology; therefore, a significant medical need exists to develop novel therapies that increase the formation of new vessels. We explored the therapeutic potential of epidermal growth factor receptor tyrosine kinase (EGFRtk) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibition in impaired ischemia-induced neovascularization in type 2 diabetes. Unilateral femoral artery ligation was performed in diabetic (db(-)/db(-)) and their control (db(-)/db(+)) mice for 4 weeks, followed by treatments with EGFRtk and ERK1/2 inhibitors (AG1478, 10 mg/kg/day and U0126, 400 μg/kg/day, respectively) for 3 weeks. Neovascularization, blood flow recovery, vascular and capillary density, and endothelial nitric oxide synthase activity were significantly impaired and were associated with enhanced EGFRtk and ERK1/2 activity in db(-)/db(-) mice. EGFRtk and ERK1/2 inhibitors did not have any effect in control mice, while in db(-)/db(-) mice there was a significant increase in neovascularization, blood flow recovery, vascular and capillary density, endothelial nitric oxide synthase activity, and were associated with a decrease in EGFRtk and ERK1/2 activity. Our data demonstrated that the inhibition of EGFRtk and ERK1/2 restored ischemia-induced neovascularization and blood flow recovery in type 2 diabetic mice. Thus, EGFRtk and ERK1/2 could be possible targets to protect from ischemia-induced vascular pathology in type 2 diabetes.ope

Editorial: Diabetes, Hypertension and Cardiovascular Diseases

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Enhanced NF-κB Activity Impairs Vascular Function Through PARP-1–, SP-1–, and COX-2–Dependent Mechanisms in Type 2 Diabetes

Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor-κB (NF-κB) signaling contributes to vascular dysfunction in T2D. We treated type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice with two NF-κB inhibitors (6 mg/kg dehydroxymethylepoxyquinomicin twice a week and 500 μg/kg/day IKK-NBD peptide) for 4 weeks. Pressure-induced myogenic tone was significantly potentiated, while endothelium-dependent relaxation (EDR) was impaired in small coronary arterioles and mesenteric resistance artery from diabetic mice compared with controls. Interestingly, diabetic mice treated with NF-κB inhibitors had significantly reduced myogenic tone potentiation and improved EDR. Importantly, vascular function was also rescued in db(-)/db(-p50NF-κB-/-) and db(-)/db(-PARP-1-/-) double knockout mice compared with db(-)/db(-) mice. Additionally, the acute in vitro downregulation of NF-κB-p65 using p65NF-κB short hairpin RNA lentivirus in arteries from db(-)/db(-) mice also improved vascular function. The NF-κB inhibition did not affect blood glucose level or body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NF-κB phosphorylation, cleaved poly(ADP-ribose) polymerase (PARP)-1, and cyclooxygenase (COX)-2 expression were increased in arteries from diabetic mice, which were restored after NF-κB inhibition and in db(-)/db(-p50NF-κB-/-) and db(-)/db(-PARP-1-/-) mice. In the current study, we provided evidence that enhanced NF-κB activity impairs vascular function by PARP-1-, Sp-1-, and COX-2-dependent mechanisms in male type 2 diabetic mice. Therefore, NF-κB could be a potential target to overcome diabetes-induced vascular dysfunction.ope

Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice

Endoplasmic reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischaemia-induced neovascularization in type II diabetes is unknown. We studied ischaemia-induced neovascularization in the hind-limb of 4-week-old db - /db- mice and their controls treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) and interleukin-1 receptor antagonist (anakinra, 0.5 µg/mouse per day) for 4 weeks. Blood pressure was similar in all groups of mice. Blood glucose, insulin levels, and body weight were reduced in db - /db- mice treated with TUDCA. Increased cholesterol and reduced adiponectin in db - /db- mice were restored by TUDCA and anakinra treatment. ER stress and inflammation in the ischaemic hind-limb in db - /db- mice were attenuated by TUDCA and anakinra treatment. Ischaemia-induced neovascularization and blood flow recovery were significantly reduced in db - /db- mice compared to control. Interestingly, neovascularization and blood flow recovery were restored in db - /db- mice treated with TUDCA or anakinra compared to non-treated db - /db- mice. TUDCA and anakinra enhanced eNOS-cGMP, VEGFR2, and reduced ERK1/2 MAP-kinase signalling, while endothelial progenitor cell number was similar in all groups of mice. Our findings demonstrate that the inhibition of ER stress and inflammation prevents impaired ischaemia-induced neovascularization in type II diabetic mice. Thus, ER stress and inflammation could be potential targets for a novel therapeutic approach to prevent impaired ischaemia-induced vascular pathology in type II diabetes.ope

MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy

The endothelium plays a pivotal role in maintaining vascular health. Obesity is a global epidemic that has seen dramatic increases in both adult and pediatric populations. Obesity perturbs the integrity of normal endothelium, leading to endothelial dysfunction which predisposes the patient to cardiovascular diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that play important roles in a variety of cellular processes such as differentiation, proliferation, apoptosis, and stress response; their alteration contributes to the development of many pathologies including obesity. Mediators of obesity-induced endothelial dysfunction include altered endothelial nitric oxide synthase (eNOS), Sirtuin 1 (SIRT1), oxidative stress, autophagy machinery and endoplasmic reticulum (ER) stress. All of these factors have been shown to be either directly or indirectly caused by gene regulatory mechanisms of miRNAs. In this review, we aim to provide a comprehensive description of the therapeutic potential of miRNAs to treat obesity-induced endothelial dysfunction. This may lead to the identification of new targets for interventions that may prevent or delay the development of obesity-related cardiovascular disease.ope

Sodium nitrite therapy rescues ischemia-induced neovascularization and blood flow recovery in hypertension

Arterial hypertension is a major risk factor that can lead to complication of peripheral vascular disease due, in part, to endothelial dysfunction. Because sodium nitrite (SN) can be converted to nitric oxide (NO), which counteracts endothelial dysfunction, we explored the effect of nitrite on neovascularization following hind limb ischemia in different models of hypertension (HT). Chronic delivery of angiotensin II (Ang II, 400 ng/kg/min) or N(omega)-nitro-L-arginine-methyl-ester (L-NAME, 0.1 g/L) was used for a 2-week period to induce hypertension. Mice were subjected to femoral artery ligation-induced ischemia in the hind limb followed by treatment with SN (50 mg/L) for 2 weeks. SN significantly reduced systolic arterial blood pressure in mice receiving Ang II and L-NAME but had no effect in sham animals. After 2 weeks, blood flow and microangiography showed 60 % ± 1.0 recovery in sham compared with 40 % ± 1.3 in HT mice. Importantly, sham and HT mice treated with SN showed a 100 % blood flow recovery associated with normalization in capillary density. The inhibition of xanthine-oxido-reductase (allopurinol) or VEGFR (SU-5416) prevented the neovascularization in HT mice treated with SN. Cyclic GMP (cGMP) content in the hind limb was significantly increased in mice treated with SN compared with non-treated mice. Nitrite/nitrate content was only increased in the sham group treated with SN. Immunoprecipitation and Western blot analysis revealed an increase in eNOS/Akt/VEGFR phosphorylation in skeletal muscle from mice treated with SN compared with non-treated mice. Our findings indicate that SN therapy rescues the neovascularization and blood flow recovery in the ischemic hind limb of sham and HT mice likely through the Akt/NO/cGMP and VEGFR pathways.ope

팀 내 구성원의 목표성향의 동시발생이 팀 혁신에 미치는 영향

학위논문 (석사)-- 서울대학교 대학원 : 경영학과, 2015. 2. 박원우.기존의 목표성향에 관련된 연구는 교육, 사회, 조직행동 등 다양한 분야에서 단일의 목표성향이 종속변수에 어떠한 영향을 미치는지를 규명했다. 기존 연구 결과는 학습지향(Learning goal orientation)이 긍정적 성과와 관련 있고, 성과지향(performance goal orientation)이 부정적 성과와 관련 있음을 밝혀왔다. 그러나 다중목표성향 관점에 입각하여, 개인이 보유하고 있는 목표성향의 동시발생이 어떻게 혁신성과에 영향을 미칠 수 있는지를 팀 수준에서 실증적으로 검증한 연구는 없었다. 본 연구에서는 팀의 혁신적인 성과를 예측하는 변수로써, 팀 내 구성원이 보유하고 있는 목표성향의 동시발생의 정도를 살펴보았다. 이때, 흡수역량(absorptive capacity)의 매개효과 및 조직의 혁신 분위기의 조절효과를 밝혀냄으로써 팀 내 구성원이 보유한 목표성향의 동시발생이 혁신에 미치는 과정을 규명하고자 한다. 먼저, 본 연구는 잠재흡수역량과 실현흡수역량을 팀 내 구성원이 보유한 목표성향의 동시발생이 팀의 혁신에 영향을 미치는 과정에서의 팀 수준 매개변수로서 제시한다. 더불어, 혁신을 위한 지원 분위기나 업무지향분위기가 상황변수로서 팀내 구성원이 보유한 목표성향의 동시발생이 흡수역량에 미치는 긍정적인 영향을 강화할 것으로 기대한다. 이 연구에서는 이러한 이론적 주장을 국내 서비스 및 제조 산업에 속한 28개 조직, 60팀을 대상으로 실증연구하였고, 가설들은 대체적으로 지지되었다.제 1장 서론 제 2장 이론적 배경 제 1절 목표성향(Goal orientation) 제 2절 목표성향의 다중목표지향관점(multiple goals perspective) 제 3절 팀의 혁신(innovation) 제 4절 흡수역량(Absorptive capacity) 제 3장 연구목적, 모형 및 가설 제 1절 연구목적 제 2절 연구모형 제 3절 연구가설 1. 팀 내 구성원의 목표성향의 동시발생(co-occurrence of goal orientation)과 팀 혁신 2. 목표성향의 동시발생과 잠재흡수역량 3. 목표성향의 동시발생과 실현흡수역량 4. 팀 내 구성원이 보유한 목표 성향의 동시발생과 실현흡수역량사이의 잠재흡수역량 매개효과 5. 실현흡수역량과 혁신 6. 잠재흡수역량과 팀의 혁신 사이의 관계의 실현흡수역량의 매개효과 7. 혁신 분위기의 조절효과 제 4장 연구방법 제 1절 연구설계 및 수행절차 제 2절 변수 측정 제 5장 연구결과 제 1절 기초분석 제 2절 가설검증 제 6장 논의 및 결론 제 1절 연구결과 요약 제 2절 연구의 시사점 제 3절 연구의 한계 및 향후 연구방향 참고문헌 부록- 설문문항 ABSTRACTMaste