Renin-angiotensin system genes as candidate genes in cardiovascular diseases

Through binding to its specific receptors, the peptide hormone angiotensin II (Ang II) has multiple actions. Among them, its ability to regulate smooth muscle cell contractility and growth, as well as sodium and water homeostasis, making Ang II a major hormone of the cardiovascular system. Polymorphic variations, affecting the function of the expression of the genes involved in Ang II generation or action, may be the basis for particular genetic predisposition to cardiovascular diseases, such as hypertension or myocardial infarction. This hypothesis is now being tested by the use of informative DNA markers on the renin-angiotensin system (RAS) genes in genetic studies involving animal models or collections of patients affected by the disease. Results available on the RAS genes are presented here together with the future extensions of the strategy for identifying genes that predispose patients to common cardiovascular diseases.     

肾素血管紧张素系统与微炎症

高血压、糖尿病、脂质代谢紊乱和肥胖常常簇集出现而形成代谢综合征,严重影响公众的健康水平。近年来,代谢性疾病的微炎症背景备受学者关注,微炎症状态与代谢性疾病的发生发展密切关联。肾素一血管紧张素系统（RAS）,除了血流动力学调节作用外,在微炎症反应中也发挥重要的作用。阻断RAS,对代谢性疾病具有一定的保护作用。目前已证实,RAS主要通过血管紧张素转换酶一血管紧张素1I-ATl受体（ACE-AnglI-ATlR）轴和ACE2-Ang（1-7）-Mas轴发挥作用,这两条途径具有相反的生物学活性,后者对前者有拈抗作用。血管紧张素Ⅱ（AngII）由血管紧张素Ⅱ受体介导通过多种机制发挥致炎作用,而Ang（1-7）可以拮抗AngII,抑制炎症反应。本文就RAS参与微炎症反应的相关机制做一综述。     

Renin-angiotensin system revisited

New components and functions of the renin-angiotensin system (RAS) are still being unravelled. The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II, still considered the main effector of RAS was believed to act only as a circulating hormone via angiotensin receptors, AT1 and AT2. Since then, an expanded view of RAS has gradually emerged. Local tissue RAS systems have been identified in most organs. Recently, evidence for an intracellular RAS has been reported. The new expanded view of RAS therefore covers both endocrine, paracrine and intracrine functions. Other peptides of RAS have been shown to have biological actions; angiotensin 2-8 heptapeptide (Ang III) has actions similar to those of Ang II. Further, the angiotensin 3-8 hexapeptide (Ang IV) exerts its actions via insulin-regulated amino peptidase receptors. Finally, angiotensin 1-7 (Ang 1-7) acts via mas receptors. The discovery of another ACE2 was an important complement to this picture. The recent discovery of renin receptors has made our view of RAS unexpectedly complex and multilayered. The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. Great expectations are now generated by the introduction of renin inhibitors. Indeed, RAS regulates much more and diverse physiological functions than previously believed.     

Renin-angiotensin system blockade and the risk of hyperkalemia in chronic hemodialysis patients

BACKGROUND: Blockade of the renin-angiotensin system by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers can cause hyperkalemia in patients with chronic renal insufficiency who are not on dialysis, but the risk of hyperkalemia in hemodialysis patients is unknown. SUBJECTS AND METHODS: We conducted a prospective study of 251 adult hemodialysis patients to determine if renin-angiotensin system blockade was associated with hyperkalemia, defined as a predialysis serum potassium concentration of 5.5 mmol/L or higher. Medication use was determined by chart review and patient interview. Predialysis serum potassium concentration was measured monthly. RESULTS: There were 367 episodes of hyperkalemia during 1877 person-months of follow-up. After adjustment for potential confounding variables and for clustering of episodes by patient, use of an ACE inhibitor or an angiotensin receptor blocker was associated with a significantly higher risk of hyperkalemia (odds ratio [OR] = 2.2; 95% confidence interval [CI]: 1.4 to 3.4). The increased risk of hyperkalemia with renin-angiotensin system blockade was seen in anuric dialysis patients (OR = 2.3; 95% CI: 1.3 to 4.2), as well as those with residual renal function (OR = 2.1; 95% CI: 1.0 to 4.1). CONCLUSION: The use of ACE inhibitors or angiotensin receptor blockers is independently associated with an increased risk of developing hyperkalemia in chronic hemodialysis patients. The serum potassium concentration should be closely monitored when these medications are prescribed for hemodialysis patients.     

肾素-血管紧张素系统与组织纤维化

肾素-血管紧张素系统（RAS）在心、脑、肾、肺等器官的组织纤维化病理过程中发挥重要作用。RAS与组织纤维化的发生、发展密切相关,血管紧张素转换酶抑制剂或血管紧张素Ⅱ的Ⅰ型受体拮抗剂可防治组织纤维化的进程。     

肾素-血管紧张素系统与肺部疾病

肾素-血管紧张素系统(renin-angiotensin system,RAS)具有调节血压和水钠平衡的生理作用.近年来,研究发现RAS在多种肺部疾病中发挥作用,例如肺动脉高压、肺纤维化、肺血栓栓塞症和急性呼吸窘迫综合征.最近发现RAS中的血管紧张素转化酶2(angiotensin-converting enzyme 2,ACE2)是SARS冠状病毒的受体,且病毒感染后ACE2下调可能是SARS患者肺损伤显著加重的原因.这些发现提示RAS与肺部疾病存在重要关系.     

Renin-angiotensin system polymorphisms and risk of hypertension: influence of environmental factors

Renin-angiotensin system (RAS) polymorphisms have been studied as candidate risk factors for hypertension with inconsistent results, possibly due to heterogeneity among various environmental factors. We analyzed the association between RAS candidate gene polymorphisms and risk of hypertension among 2722 women and also explored whether these associations varied according to menopausal status, body mass index, and dietary factors. In a main-effects analysis of all 2722 women adjusted for age and race, homozygosity for the AT1R A1166C polymorphism was associated with hypertension (odds ratio, 1.35; 95% confidence interval [CI], 1.03-1.78). We also found that a novel nonsense polymorphism in the aminopeptidase-A gene was associated with hypertension among postmenopausal women (hazard ratio, 1.54; 95% CI, 1.01-2.37), women with inadequate calcium intake (hazard ratio, 2.47; 95% CI, 1.29-4.72) and, marginally, women with inadequate vitamin D intake. In addition, angiotensin-converting enzyme and AT1R A1166C polymorphisms were associated or marginally associated with incident hypertension among postmenopausal women and those with inadequate calcium and vitamin D intakes. These data suggest that demographic and dietary factors may influence the associations between RAS polymorphisms and hypertension and could explain heterogeneity in prior studies.     

肾素-血管紧张素系统与糖尿病脑病

肾素-血管紧张素系统是体内重要的内分泌系统之一,通常认为其功能主要是调节血压和保持水电解质平衡.但近年的研究证实该系统还参与学习、记忆等认知功能的调节,并在糖尿病脑病的发病过程中发挥重要作用.例如:血管紧张素(Ang)Ⅱ可以抑制乙酰胆碱的释放、抑制长时程增强(LTP)的诱导、干扰胰岛素的信号转导、激活体内的氧化应激以及减少中枢的血供;AngⅣ可以促进乙酰胆碱的释放,易化LTP;Ang-(1-7)可以易化LTP,还能改善中枢血流.这些发现为糖尿病脑病的防治提供了新思路.     

肾素-血管紧张素系统与肺动脉高压

肺动脉高压(pulmonary hypertension,PH)是一种由异源性疾病和不同发病机制引起的,以肺动脉压力增高为表现的疾病状态,严重者可出现右心衰竭。目前的治疗方式虽然可缓解 PH 患者的部分症状,并在一定程度上延长患者的寿命,但 PH 仍然是一种死亡率极高的疾病,所以亟需发现新的安全有效的治疗方法。研究表明,肾素-血管紧张素系统(renin-angiotensin system,RAS)参与了 PH 的发病过程。该系统由促进血管收缩及增殖的血管紧张素转换酶-血管紧张素Ⅱ-血管紧张素Ⅱ受体1(angiotensin converting enzyme-angiotensinⅡ-angiotensinⅡ receptor 1,ACE-AngⅡ-AT1R)轴与抗血管收缩及增殖的血管紧张素转换酶2-血管紧张素(1-7)-Mas[angiotensin converting enzyme 2-angiotensin (1-7)-Mas,ACE2-Ang-(1-7)-Mas]轴组成。ACE-AngⅡ-AT1R 轴是促进 PH 病情发展的重要机制,而ACE2-Ang-(1-7)-Mas 轴因可以拮抗 ACE-AngⅡ-AT1R 轴的作用,成为 PH 治疗的研究热点。     

肾素-血管紧张素系统与糖尿病

肾素-血管紧张素系统(RAS)在糖尿病的发生、发展中有重要作用.今年的国际糖尿病联盟(IDF)第20次学术会议专题报道了糖尿病人群的RAS系统.简而言之,最有效的延缓糖尿病肾病进展的途径是阻滞RAS.大量临床研究也已经证实了阻滞RAS治疗糖尿病肾病的疗效.肾素抑制途径的研究,为防治肾损害提供了一个新的治疗方向.     

肾素-血管紧张素系统与2型糖尿病

组织局部存在肾素-血管紧张素系统（RAS）。RAS活化可加重外周组织胰岛素抵抗,并影响胰岛的形态与功能。其可能机制是影响交感神经活性、血流动力学、炎症反应、氧化应激以及王惠芳细胞增殖与凋亡等。通过使用血管紧张素转换酶抑制剂（ACEI）和血管紧张素Ⅱ受体阻断剂（ARBs）阻断RAS,可以改善胰岛素抵抗与胰岛功能,从而逆转糖耐量异常或改善糖代谢紊乱状态。     

Renin-angiotensin system in diabetic nephropathy

The importance of the renin angiotensin system (RAS) in the development and progression of the diabetic nephropathy is confirmed with the recent demonstration that the development of nephropathy in the diabetic patients can be avoided by blockers of the RAS. For that reason, the promotion of preventive programs for the detection of microalbuminuria, from the early phases of the diabetes is needed. Control of blood pressure, of glucose and lipids are needed. If microalbuminuria is present, the administration of a blocker of RAS, even in the presence of normal blood pressure can prevent the progression to diabetic nephropathy. The main objective to prevent the development and progression of nephropathy in the diabetic patients, as well as the cardiovascular risk, is a strict control of the PA.     

Renin-angiotensin system gene polymorphisms: assessment of the risk of coronary heart disease

BACKGROUND: Renin-angiotensin system genes are candidate genes in cardiovascular system diseases. Angiotensinconverting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R) gene polymorphisms are considered risk factors in coronary heart disease (CHD). AIM: To evaluate the involvement of the ACE, AGT and AT1R genetic variants in predisposition to CHD as well as their association with other known risk factors. METHODS: The study included 400 male subjects (200 with CHD and 200 healthy individuals). Genotypes were determined by a polymerase chain reaction (PCR). For the AGT and AT1R genes a restriction analysis of the PCR product was performed. The allele frequency and genotype distribution were compared between groups. RESULTS: The allele and genotype frequencies of the ACE gene were similar in both groups, however, a significantly higher frequency of the DD genotype was observed in the presence of hyperlipidemia (39% vs 24% in non-hyperlipidemic subjects, p<0.01). The AGT gene polymorphism was associated with the development of CHD. The T allele was significantly more frequent in patients than in the control group (55% vs 44%, p<0.05). The heterozygous MT genotype was observed in 61% of patients compared to 40% in the controls (p<0.05). The A1166C polymorphism of the AT1R gene was also associated with CHD as well as with age at the onset of disease. The frequency of the C allele was 29% compared to 21% in the control group (p<0.01) and the frequency of the CC homozygote was almost three times higher in patients. CONCLUSIONS: There is an association between molecular variants of the angiotensinogen and angiotensin II type 1 receptor and increased risk of CHD. The DD genotype of the ACE gene polymorphism and the TT genotype of the AGT gene polymorphism were significantly more frequent in patients with hyperlipidemia. The TT genotype of the AGT gene M235T polymorphism was associated with an increased risk of CHD and myocardial infarction only in smokers.