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Inflammation, oxidative stress and renin angiotensin system in atherosclerosis

World Journal of Biological Chemistry 2015年第3期6卷 209-217页

作者： Kazim Husain Wilfredo Hernandez Rais A Ansari Leon Ferder Department of Physiology Pharmacology and Toxicology Ponce School of Medicine Department of Biochemistry Ponce School of Medicine Department of Pharmaceutical Sciences College of Pharmacy Nova Southeastern University

Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin Ⅱ(Ang Ⅱ) and a decrease in nitric oxide. The renin-angiotensin system(RAS), and its primary mediator Ang Ⅱ, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors(angiotensin-converting enzyme inhibitors)], Ang Ⅱ receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in Apo E-deficient atherosclerotic mice.

关键词： Atherosclerosis renin-angiotensin system Inflammation Oxidants/antioxidants imbalance Antiinflammatory drugs renin-angiotensin system blockers

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Calcium channel blocker monotherapy versus combination with reninangiotensin system inhibitors on the development of new-onset diabetes mellitus in hypertensive Korean patients

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Journal of Geriatric Cardiology 2019年第6期16卷 439-447页

作者： Yong Hoon Kim Ae-Young Her Seung-Woon Rha Byoung Geol Choi Se Yeon Choi Jae Kyeong Byun Yoonjee Park Dong Oh Kang Won Young Jang Woohyeun Kim Woong Gil Choi Tae Soo Kang Jihun Ahn Sang-Ho Park Ji Young Park Min-Ho Lee Cheol Ung Choi Chang Gyu Park Hong Seog Seo Division of Cardiology Department of Internal Medicine Kangwon National University School of Medicine Chuncheon South Korea Cardiovascular Center Korea University Guro Hospital Seoul South Korea Department of Medicine Korea University Graduate School Seoul South Korea Cardiology Department Konkuk University Chungju Hospital Chungju South Korea Department of Internal Medicine Cardiovascular Division Dankook University Hospital Cheonan South Korea Department of Cardiology Soonchunhyang University Gumi Hospital Gumi South Korea Cardiology Department Soonchunhyang University Cheonan Hospital Cheonan South Korea Division of Cardiology Department of Internal Medicine Cardiovascular Center Nowon Eulji Medical Center Eulji University Seoul South Korea Department of Cardiology Soonchunhyang University College of Medicine Seoul South Korea

Background In real practice, two or more antihypertensive drugs are needed to achieve target blood pressure. We investigated the comparative beneficial actions of combination therapy of renin-angiotensin system inhibitors (RASI), with calcium channel blockers (CCB) over CCB monotherapy on the development of new-onset diabetes mellitus (NODM) in Korean patients during four-year follow-up periods. Methods A total of 3208 consecutive hypertensive patients without a history of diabetes mellitus who had been prescribed CCB were retrospectively enrolled from January 2004 to December 2012. These patients were divided into the two groups according to the additional use of RASI (the RASI group, n = 1221 and the no RASI group, n = 1987). Primary endpoint was NODM, defined as a fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%. Secondary endpoint was major adverse cardiac events (MACE) defined as total death, myocardial infarction (MI) and percutaneous coronary intervention (PCI). Results After propensity score-matched (PSM) analysis, two propensity- matched groups (939 pairs, n = 1878, C-statistic = 0.743) were generated. The incidences of NODM (HR = 1.009, 95% CI: 0.700–1.452, P = 0.962), MACE (HR = 0.877, 95% CI: 0.544–1.413, P = 0.589), total death, MI, PCI were similar between the two groups after PSM during four years. Conclusions The use of RASI in addition to CCB showed comparable incidences of NODM and MACE compared to CCB monotherapy in non-diabetic hypertensive Korean patients during four-year follow-up period. However, large-scaled randomized controlled clinical trials will be required for a more definitive conclusion.

关键词： Calcium channel blocker Diabetes mellitus renin-angiotensin system inhibitors

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angiotensin-Converting Enzyme 2 in the Rostral Ventrolateral Medulla Regulates Cholinergic Signaling and Cardiovascular and Sympathetic Responses in Hypertensive Rats

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Neuroscience Bulletin 2019年第1期35卷 67-78页

作者： Yu Deng Xing Tan Miao-Ling Li Wei-Zhong Wang Yang-Kai Wang Department of Physiology Second Military Medical UniversityShanghai 200433China Institution of Polar Medicine Research Center Second Military Medical UniversityShanghai 200433China Department of Anesthesiology Changhai HospitalShanghai 200433China Institute of Cardiovascular Medical Research Southwest Medical UniversityLuzhou 646000China

The rostral ventrolateral medulla(RVLM) is a key region in cardiovascular regulation. It has been demonstrated that cholinergic synaptic transmission in the RVLM is enhanced in hypertensive rats. angiotensinconverting enzyme 2(ACE2) in the brain plays beneficial roles in cardiovascular function in hypertension. The purpose of this study was to determine the effect of ACE2 overexpression in the RVLM on cholinergic synaptic transmission in spontaneously hypertensive rats(SHRs).Four weeks after injecting lentiviral particles containing enhanced green fluorescent protein and ACE2 bilaterally into the RVLM, the blood pressure and heart rate were notably decreased. ACE2 overexpression significantly reduced the concentration of acetylcholine in microdialysis fluid from the RVLM and blunted the decrease in blood pressure evoked by bilateral injection of atropine into the RVLM in SHRs. In conclusion, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced cholinergic synaptic transmission in SHRs.

关键词： Hypertension renin-angiotensin system Gene transfer Acetylcholine Sympathetic nerve activity

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Effects of AT1 receptor antagonist,Iosartan,on rat hepatic fibrosis induced by CCl_4

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World Journal of Gastroenterology 2000年第4期6卷 540-545页

作者： Hong Shan Wei Ding Guo Li Han Ming Lu Yu Tao Zhan Zhi Rong Wang Xin Huang Jing Zhang Ji Lin Cheng Qin Fang Xu Department of Gastroenterology,Xinhua Hospital,Shanghai Second Medical University,Shanghai 200092,China 上海第二医科大学上海

AIM To investigate effect of losartan,an AT1receptor antagonist,on hepatic fibrosis induced byCCl;and to determine whether or not AT1receptors are expressed on hepatic stellate cells,METHODS AND RESULTS Fifty male Sprague-Dawley rats,weighing（180±20）g,wererandomized into five groups（control group,modelgroup,and three losartan treated groups）,inwhich all rats were given the subcutaneousinjection of 40% CCl4（every 3 days for 6 weeks）except for rats of control *** of losartan-treated groups were treated with losartan（20 mg/kg,10 mg/kg,5 mg/kg,daily gavage）,After 6weeks liver tissue and serum samples of all ratswere *** hyaluronic acid（HA）,procollagen typeⅢ（PCⅢ）were detected byradioimmunoassays,van Giesion collagen stainingwas used to evaluate the extracellular matrix of ratswith liver *** expression of AT1receptors,transforming growth factor-beta（TGF-β）,and alpha-smooth muscle actin（a-SMA）inliver tissue were determined byimmunohistochemical *** withmodel group,serum ALT and AST of losartan-treated groups were significantly reduced（t=4.20,P4.The mechanism may be related tothe decrease in the expression of AT1 receptorsand TGF-β,ameliorating the injury of hepatocytes;activation of local renin-angiotensin system mightrelate to hepatic fibrosis;and during progressionof fibrosis,activated hepatic stellate cells mightexpress AT1 receptors.

关键词： liver cirrhosis/drug therapy renin-angiotensin system angiotensin Ⅱ type 1 receptor antagonist losartan

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Roles and functions of Atp6ap2 in the brain

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Neural Regeneration Research 2018年第12期13卷 2038-2043页

作者： Alexander Bracke Oliver von Bohlen und Halbach Institute of Anatomy and Cell Biology Universit?tsmedizin Greifswald

The classical renin-angiotensin system（RAS） in the body has been studied intensively in the last decades, since it is known that this system is involved in the regulation of blood pressure. Since nearly all members of the classical RAS have also been identified within the brain in the last decades and due to the existence of the blood-brain barrier, a RAS within the brain（bRAS） that is largely independent from the peripheral RAS has been postulated. All members of the angiotensin family as e.g., angiotensin II, angiotensin IV and angiotensin II（1-7） along with the respective receptors（e.g., angiotensin II receptor type 1（AT1）, angiotensin II receptor type 2（AT2）, angiotensin IV receptor（AT4）, angiotensin II（1-7） receptor（Mas）） have been identified within the brain. Moreover, a receptor capable of binding renin and the renin precursor prorenin with high affinity has also been detected within the brain. This protein functions as a membrane receptor for（pro）renin and also represents a V-ATPase subunit and is therefore termed（P）RR or Atp6 ap2, respectively. In this review we shed light on the（known as well as putative） roles and functions of Atp6 ap2 in the brain under physiological and pathophysiological conditions.

关键词： prorenin receptor renin-angiotensin X-linked intellectual disability hippocampus behaviour adult neurogenesis animal model human

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Dynamic Variation of RAS on Silicotic Fibrosis Pathogenesis in Rats

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Current Medical Science 2019年第4期39卷 551-559页

作者： Bo-nan ZHANG Xin ZHANG Hong XU Xue-min GAO Gui-zhen ZHANG Hui ZHANG Fang YANG School of Public Health Tangshan Key Laboratory for Clinical and Basic Research on Chronic DiseasesSchool of Basic Medical SciencesNorth China University of Science and TechnologyTangshan 063210China Hebei Key Laboratory for Organ Fibrosis Medical Research CenterTangshan Key Laboratory for Clinical and Basic Research on Chronic DiseasesSchool of Basic Medical SciencesNorth China University of Science and TechnologyTangshan 063210China Hebei Key Laboratory for Chronic Diseases Tangshan Key Laboratory for Clinical and Basic Research on Chronic DiseasesSchool of Basic Medical SciencesNorth China University of Science and TechnologyTangshan 063210China Basic Medical College Hebei Medical UniversityShijiazhuang 050017China

The dynamic variation of renin-angiotensin system (RAS) in silicosis remains *** Wistar rats were divided into 7 groups including control group,silicosis groups (inhaling SiO2 for 2,4,8,16 and 24 weeks,respectively) and Captopril (Cap) *** lung primary fibroblasts were divided into control group,SiO2-stimulated group (0,0.5,1,3,6,12,24 and 48 h) and Cap *** silicotic nodules were formed and collagens were deposited gradually in silicosis group observed by haematoxylin and eosin (HE) staining and Van Gieson (VG) *** relieved the lung fibrosis and collagen *** indicated the positive expression of α-smooth muscle actin α-SMA) was increased gradually in silicotic rat lung *** blotting revealed the expression of collagen type Ⅰ(Col Ⅰ) and α-SMA was up-regulated in silicotic rat lung tissue and fibroblasts stimulated by *** decreased the expression of Col Ⅰ and α-SMA in silicotic rat lung tissue and fibroblasts stimulated by *** blotting also demonstrated the expression of angiotensin-converting enzyme (ACE) and angiotensin Ⅱ type 1 receptor (ATI) was increased,and the expression of ACE2 and Mas was decreased gradually in silicotic rat lung tissue and fibroblasts stimulated by *** showed the serum levels of ACE and angiotensin Ⅱ(Ang Ⅱ) were also increased and ACE2 and Ang (1 -7) were decreased in the silicosis *** with Cap decreased the expression levels of ACE,Ang Ⅱ and ATI,and increased the expression levels of ACE2,Ang (1-7) and *** findings suggested that an imbalance between ACE-Ang Ⅱ-AT1 axis and ACE2-Ang (l-7)-Mas axis may participate in the development of silicosis.

关键词： silicosis fibroblasts SiCh renin-angiotensin system α-smooth muscle actin

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Gender differences in development of renovascular hypertension

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中国药理学通报 2015年第B11期31卷 147-148页

Aim The aim of this investigation was to evaluate gender differences in development of renovascular hy- pertension. Methods The experiments were performed with 10-week-old Sprague-Dawley rats which were prepared by the narrow side of the renal artery to development renovascular hypertension （2K1C）. After 32 weeks of regular feeding, rats were instrumented to determine blood pressure in anesthesia state. The blood was collecting for determi- nation of Anglland ET-1 by using ELISA kit. The thoracic aorta were isolated and snap frozen in liquid nitrogen. Ap- plications Western Blot method to detect tissue protein expression of angiotensin-converting enzyme （ACE1, ACE2）, and Angllreceptor（AT1 R, AT2 R）. Results SBP and DBP were higher in 2K1 C-females than in 2K1 C-males [ SBP：（ 172 ± 19. 2） vs （ 157 ± 16. 4） mmHg , P 〈0. 01. DBP： 138 ± 15.4 vs 128 ± 15.5, P 〈0. 05, n =20]. Plasma AngII were higher in 2K1C-males [ （ 11.2 ±2. 87） vs （9.60 ±3.51 ） ng · L^-1, P 〈0. 05] , and ET-1 were higher in 2K1C- females （38.77 ± 17.99 vs 33.76 ± 17.50 ng · L^-1, P 〈0. 05） . In thoracic aorta tissue, the protein levels of ACE1 and ACE2 were increased in 2K1C-females （ACE1 ： 1. 204 ＋0. 258 vsl. 182 ±0. 209, ACE2： 2. 431 ±0. 214 vs 1. 528±0.130, P 〈0.01）, AT1R were increased in 2K1C-males （0.955 ±0.201 vs 0.841 ±0.176, P 〈0.05）, ATzR were increased in 2K1C-females （2. 464±0. 142 vs 1. 431±0. 062, P 〈0. 01）. In kidney tissue, the protein levels of ACE1 were increased in 2K1C-females （2. 023 ＋0. 144 vs 1. 079±0. 103, P 〈0. 01）, ACE2 were increased in 2K1C- males （2. 496 ±0. 314 vs 1. 706±0. 214, P 〈0. 05）, AT2R and ATzR were increased in 2K1C-males （AT2R：0. 867 ±0. 092 vs O. 685±0. 176, P 〈0. 05, ATzR： 1. 413 ± 0. 233 vs 1. 146 ±0. 146, P 〈0. 05）. In heart tissue, the pro- tein levels of ACE1 were increased in 2K1 C-females （1. 122 ± 0. 177 vs O. 793± 0. 125, P 〈 0. 05） , ACE2 were no difference （0. 682 ±0. 108 vs O. 654 ±0. 103）, AT2R were increased in 2K1C-females （1. 478 ± 0. 235 vs 1.

关键词： estrogen, hypertension renin-angiotensin system angiotensin-converting enzyme Angll receptor ET-1

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Management of nephropathy in patients with type 2 diabetes

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Chinese Medical Journal 2002年第1期115卷 129-135页

作者： Critchley JA Zhao HL Tomlinson B Leung W Thomas GN Chan JC Cockram CS Chinese Univ Hong Kong Prince Wales Hosp Dept Med & Therapeut Div Clin Pharmacol Shatin Hong Kong Peoples R China

Purpose To review evidence-based management of nephropathy in patients with type 2 *** sources A literature search (MEDLINE 1966 to 2000) was performed using the key word 'diabetic nephropathy'. Relevant book chapters were also *** selection Well-controlled, prospective landmark studies and expert review articles on diabetic nephropathy were *** extraction Data and conclusions from the selected articles that provide solid evidence to the optimal management of diabetic nephropathy were extracted and interpreted in light of our clinical research experience with many thousands of Hong Kong Chinese *** Hypertension, long diabetes duration, poor glycaemic control and central obesity are the most important risk factors. Microalbuminuria is a practical marker to predict overt nephropathy in type 2 diabetic patients. Risk factor modification, renal function monitoring and combined therapies are the current integrated approaches to manage patients with diabetic kidney disease. Optimal glycaemic control is the mainstay of treatment but effective antihypertensive therapy is also key to delaying the progression of diabetic nephropathy. angiotensin-converting enzyme inhibitors and angiotensin Ⅱ receptor antagonists have important renoprotective actions independent of their blood pressure lowering actions. Conclusions Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. Monitoring renal function and screening for microalbuminuria will allow the identification of patients with nephropathy at a very early stage for intervention. Tight glycaemic control and aggressive antihypertensive treatment as well as the use of renin-angiotensin system inhibitors should substantially delay the progression of nephropathy.

关键词： type 2 diabetes · nephropathy · albuminuria · hypertension · renin-angiotensin system

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The regulatory role of AT 1 receptor on activated HSCs in hepat,c fibrogenesis,effects of RAS inhibitors on hepatic fibrosis induced by CCl_4

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World Journal of Gastroenterology 2000年第6期6卷 824-828页

作者： Hong Shan Wei Han Ming Lu Ding Guo Li Yu Tao Zhan Zhi Rong Wang Xin Huang Ji Lin Cheng Qin Fang Xu Department of Gastroenterology,Xinhua Hospital,Shanghai Second Medical University,Shanghai 200092,China

AIM To assess the effect of ACE inhibitor andAng Ⅱ type Ⅰ（AT1）receptor antagonist inpreventing hepatic fibrosis caused by CCl4administration in rats;to investigate whether ornot there are expression of AT 1 receptors onhepatic stellate cells;and to observe the effectof Ang Ⅱ on proliferation and ECM synthesis ofcultured *** Studies were conducted in maleSprague-Dawley *** for thehepatofibrotic model group and the controlgroup,in three treated groups,either enalapril（5 mg/kg）,or Iosartan（10 mg/kg）,or enalapril+Iosartan were given to the fibrotic rats bydaily gavage,and saline vehicle was given tomodel and normal control *** 6 weeks,liver fibrosis was assessed directly by hepaticmorphometric analysis,which has beenconsidered the gold standard for thequantification of *** expressions of AT1 receptors and（α-mooth muscle actin,α-SMA）in liver tissue or isolated hepatic stellate cells（HSCs）were detected by *** effect of Ang Ⅱ on HSCproliferation was determined by MTT *** of Ang Ⅱ on collagen synthesis of HSCswas determined by 3H-proline *** Contrasted to the fibrosis in rats ofthe model group,groups of rats treated with either enalapril or Iosartan,or a combination oftwo drugs showed a limited expansion of theinterstitium（4.23±3.70 vs 11.22±4.79,P0.05）.Expression of AT 1receptors was found in fibrotic interstitium offibrotic rats,whereas in normal control rats theywere limited to vasculature only to a very *** 1 receptors were also expressed onactivated HSCs in the *** concentrationsfrom 10-9to 10-5mol/L,Ang Ⅱ stimulated HSCproliferation in culture in a *** Ang Ⅱ concentrationsproduced corresponding increases in 3*** among groups were ***

关键词： renin-angiotensin system liver cirrhosis enalapril extracellular matrix immunohistochemistry losartan liver/injuries

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Hypertension, type Ⅳ cardiorenal syndrome and chronic kidney disease: Pathophysiological and therapeutical approach

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World Journal of Hypertension 2017年第1期7卷 10-18页

作者： Luca Di Lullo Antonio Bellasi Antonio De Pascalis Department of Nephrology and Dialysis L. Parodi-Delfino Hospital Department of Nephrology and Dialysis ASST Lariana Department of Nephrology Dialysis and Transplantation V. Fazzi Hospital

Hypertension represent one of the most important comorbid factors in chronic kidney disease(CKD) patients and its prevalence increases from 65% to 95% according to glomerular filtration rate decline. CKD patients need to maintain their blood pressure levels into 130/80 mm Hg according to most recent guidelines. Despite of many therapeutic agents, achievement of ideal blood pressure levels remains so far from the ideal ones. Hypertensive disease represent most important risk factor to develop a type Ⅳ cardiorenal syndrome, while prevalence of end stage renal disease is still raising and it represents worldwide epidemiological challenge. Correct management of hypertensive disease can obtain better control on CKD progression.

关键词： Hypertension TypeⅣcardiorenal syndrome renin-angiotensin system inhibitors Calcium channel blockers Chronic kidney disease

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