ACE2和ACE在自发性高血压大鼠心肌中的变化

目的:观察自发性高血压大鼠(SHR)心肌的血管紧张素转化酶(ACE)和ACE2的表达,以探讨ACE2和ACE在高血压发生发展中的变化。方法:取15只SHR,处死,分离左心室,行RT-PCR、Western blot蛋白质免疫印迹和免疫组织化学检测ACE及ACE2表达;同步取10只WKY大鼠作为正常血压对照组。结果:SHR组心肌ACE的mRNA和蛋白质表达都显著高于WKY组[(1.68±0.34)∶(0.33±0.12),P<0.05;(1.21±0.14)∶(0.71±0.11),P<0.05],而ACE2的mRNA和蛋白质表达皆明显低于WKY组[(0.50±0.15)∶(1.16±0.24),P<0.05;(0.71±0.24)∶(1.22±0.14),P<0.05)]。免疫组织化学染色显示,SHR组ACE的阳性率明显高于WKY组(87%∶50%,P<0.05),而ACE2的阳性率明显低于WKY组(27%∶70%,P<0.05)。结论:SHR心肌ACE明显升高,ACE2显著降低;SHR高血压发生发展过程中存在着ACE和ACE2表达的失衡。     

血管紧张素转化酶Ⅱ与血管紧张素转化酶在胰腺癌组织中的表达水平变化及相互关系

目的检测血管紧张素转化酶Ⅱ(ACE2)和血管紧张素转化酶(ACE)在人胰腺癌组织中的表达情况及相互间关系。方法采用逆转录-聚合酶链反应(RT-PCR)方法检测ACE2与ACE mRNA在14例胰腺癌患者的癌组织、癌旁组织(距癌边缘>5 cm)中的表达及两者的关联性;采用免疫组化法检测ACE2与ACE蛋白在92例胰腺癌患者的癌组织中的表达水平,统计分析两者表达的关联性及ACE2与胰腺癌临床病理特征的关系。结果 ACE2 mRNA在胰腺癌组织中的相对表达量显著低于癌旁组织,ACE mRNA在癌组织中的相对表达量则显著高于癌旁组织(P值均<0.05);ACE2蛋白在胰腺癌组织中的阳性表达率为22.8%(21/92),显著低于癌旁胰腺组织[57.6%(53/92),P<0.05];ACE在胰腺癌中的阳性表达率[85.9%(79/92)]则显著高于癌旁胰腺组织[44.6%(41/92),P<0.05]。胰腺癌组织中ACE2表达在基因及蛋白水平均与ACE表达呈负相关性(r值分别为-0.416和-0.475,P值均<0.05)。胰腺癌组织中ACE2蛋白的表达与胰腺癌的TNM分期密切相关(P<0.05)。结论 ACE2在胰腺癌中表达下调及ACE2与ACE表达比例失衡可能在胰腺癌的发生发展中起重要作用。     

Signaling by the angiotensin-converting enzyme

Inhibition of the angiotensin-converting enzyme (ACE) protects against the progression of several cardiovascular diseases. Because of its dual role in regulating angiotensin II and bradykinin levels, the positive clinical effects of ACE inhibitors were thought to be the consequence of concomitant reductions in the production of angiotensin II and the degradation of bradykinin. Recent evidence suggests that some of the beneficial effects of ACE inhibitors on cardiovascular function and homeostasis can be attributed to novel mechanisms. These include the accumulation of the ACE substrate N-acetyl-seryl-aspartyl-lysyl-proline, which blocks collagen deposition in the injured heart, as well as the activation of an ACE signaling cascade that involves the activation of the kinase CK2 and the c-Jun N-terminal kinase in endothelial cells and leads to changes in gene expression. Moreover, at least one other ACE homologue (ACE2) is proposed to counteract the detrimental effects associated with the activation of the classical renin-angiotensin system. These data reveal hitherto unexpected levels of internal regulation of the renin-angiotensin system.     

Renal response to angiotensin-converting enzyme inhibition

Angiotensin-converting enzyme inhibitors, both teprotide and captopril, induce a potentiated renal vascular response in patients with essential hypertension, and with that a consistent increase in sodium excretion and occasionally an increase in glomerular filtration rate. In patients with advanced congestive heart failure resistant to other vasodilators, a similar triad occurs. It is not yet clear in which settings the renal response to angiotensin-converting enzyme inhibition reflects a reduction in angiotensin II formation—thus implicating the renin-angiotensin system in the pathogenesis—or an additional action, such as a potentiation of the local actions of bradykinin or enhanced prostaglandin formation. Under some circumstances, especially where a qualitatively and quantitatively similar response occurs to angiotensin antagonists and angiotensin-converting enzyme inhibitors or where an angiotensin antagonist prevents an additional response to a converting enzyme inhibitor, it is clear that the specific action of the converting enzyme inhibitor on angiotensin II formation is responsible. Unfortunately, for most responses in animal models and all responses in patients, such rigorous evidence is not yet available.     

Pharmacotherapy review: angiotensin-converting enzyme inhibitors

On inspection of most treatment algorithms for hypertension, it is apparent that multiple drug classes are available. In choosing a medication class for hypertension therapy, nuances of the selection process often go unappreciated. This article is the first in a series describing important pharmacotherapeutic considerations of the individual drug classes used in the treatment of hypertension.     

Clinical applications of angiotensin-converting enzyme inhibitors

Although only recently introduced, angiotensin-converting enzyme inhibitors have been utilized to treat a wide variety of clinical disorders. Their uses to date, approved by the Food and Drug Administration, have been in the treatment of refractory hypertension and congestive heart failure. However, they have been evaluated with mixed results in numerous other conditions in which the renin-angiotensin-aldosterone system may play a role. Their current status in the treatment of hypertension, congestive heart failure, and these other conditions is reviewed.     

Phosphorus-containing inhibitors of angiotensin-converting enzyme.

Several phosphonamides, phosphoramides, and phosphates having the general structure R-Y-P(O)(OH)-X-CH(CH3)-CO-Pro have been synthesized and tested for inhibition of angiotensin-converting enzyme (dipeptidyl carboxypeptidase; peptidyl-dipeptide hydrolase, EC 3.4.15.1). Inhibition was found to depend on the nature of R, Y, and X such that the maximal effect was observed when X = NH, Y = CH2, and R = phi CH2 (50% inhibition at 7 nM). Substitution of CH2 or O at X and O at Y produced significantly less potent inhibitors. Groups shorter or longer than R = phi CH2 led to less active inhibitors, presumably due to nonoptimal interaction of the side chain with the S1 subsite.     

High expression of angiotensin-converting enzyme and angiotensin-converting enzyme 2 in preservation injury after liver transplantation in rats

Aim:  To explore the possible role of local renin-angiotensin system (RAS) in preservation injury (PI) after liver transplantation by studying expression of angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) in the transplanted liver of rats and its relationship with PI.
Methods:  The animals receiving liver transplantation were assigned to cold preservation group (CP group) and non-cold preservation group (NCP group). The sham-operation group was used as the control. The severity of PI was assessed by histology. The mRNA and protein expressions of ACE and ACE2 were detected by real-time PCR, Western blot, respectively. Tissue hypoxia was assessed by pimonidazole staining.
Results:  Various degrees of tissue injury were observed after liver transplantation, especially in CP group. ACE2 mRNA and protein expressions in the transplantation groups were elevated significantly compared with those of the control group ( P  < 0.01, P  < 0.05), and higher in CP group than those in NCP group ( P  < 0.05). There was a close positive correlation between PI and mRNA expression of ACE and ACE2. Positive pimonidazole staining distributed around the hepatic central vein, and became darker and more extensive with deterioration of PI.
Conclusion:  ACE2 was closely related to tissue hypoxia due to CP-induced PI of the transplanted liver, and ACE may aggravate the inflammation in PI. Local RAS may play an important role in PI of the transplanted liver.     

Elevated serum angiotensin-converting enzyme activity in onchocerciasis

Our objective was to measure serum angiotensin-converting enzyme (ACE) activity in patients with onchocerciasis. Serum ACE activity is commonly used in the diagnosis and follow-up of patients with sarcoidosis. However, serum ACE activity can also be elevated in a number of other granulomatous disorders. In onchocerciasis, a parasitic disease affecting millions of people in Africa and Central and South America, granulomatous tissue around adult worms has been identified, yet raised serum ACE activity has not been reported so far. We measured serum ACE activity in serum samples from 42 onchocerciasis patients and 39 endemic controls previously enrolled in two studies concerning the side effects after ivermectin treatment in Sierra Leone, West Africa. The mean ACE activity in the patient group was 53.8 units/liter (S.D. 19.8) compared with 35.2 units/liter (S.D. 14.0) in the control group (p < 0.0001). Nine of 42 patients had elevated ACE activity (mean of the endemic controls ± 2 S.D.) compared with 1 of 39 controls (p = 0.01). Sensitivity and specificity of elevated ACE in serum from onchocerciasis patients from Sierra Leone was 21 and 97%, respectively. ACE activity was not related to the microfilarial skin load or development of side effects after ivermectin treatment. Serum ACE activity can be elevated in onchocerciasis. Clinicians should be aware of this phenomenon when determining serum ACE activity in persons from endemic areas. Offprint requests to: Marjolein J. H. Ronday     

Antisense oligodeoxynucleotide inhibition of vascular angiotensin-converting enzyme expression attenuates neointimal formation: evidence for tissue angiotensin-converting enzyme function

It has been proposed that vascular angiotensin-converting enzyme (ACE) plays an important role in regulating vascular growth. Indeed, ACE inhibitors have been reported to prevent neointimal formation after vascular injury in a rat carotid artery model. However, classic pharmacological experiments cannot exclude the potential contributions of hemodynamics and the circulating renin-angiotensin system (RAS). In this study, we used antisense oligodeoxynucleotide (ODN) to obtain local blockade of vascular ACE expression without effects on systemic hemodynamics and circulating RAS. To increase the effectiveness of antisense action, we modified the hemagglutinating virus of Japan-liposome ODN delivery method by cotransfection with nuclear protein (high mobility group 1 [HMG-1]) and RNase H. In vitro experiments showed the enhanced efficacy of antisense ODN by cotransfection of HMG-1 and RNase H compared with ODN alone. In vivo transfection of antisense ACE ODNs into intact uninjured rat carotid artery resulted in a significant reduction of vascular ACE activity, and cotransfection of HMG-1 and RNase H showed further reduction. We examined the effects of local blockade of vascular ACE expression on neointimal formation after vascular injury. Transfection of antisense ACE ODNs resulted in the attenuation of neointimal formation, whereas sense and scrambled ODNs did not. Blood pressure, heart rate, and serum ACE activity were not affected by antisense treatment. The magnitude of vascular ACE inhibition correlated with the suppression of the neointimal size. Overall, this study demonstrates that local antisense ODN inhibition of vascular ACE expression attenuates neointimal formation independent of hemodynamics and circulating RAS. The results support the existence of a functional tissue angiotensin system in the rat vessel wall.