Vascular Angiotensin-converting Enzyme Research Articles

Managing hypertension using brewing bioactive peptides as angiotensin-converting enzyme inhibitors: Impact on vascular tone through ex vivo assays

BackgroundPeptides derived from brewer’s spent grain (BSG) and yeast (BSY) are promising natural substitutes of synthetic drugs to manage hypertension as inhibitors of angiotensin-converting enzyme (ACE). However, their impact on the vascular function, so far, remains to be verified. Accordingly, we aimed to evaluate the effect of brewing peptides on the arterial vasocontractile response to angiotensin (Ang) I (through vascular ACE-inhibition) to estimate their antihypertensive potential. The impact of the oral route (gastrointestinal digestion, intestinal absorption, and liver metabolism) in brewing peptides was also investigated. MethodsIliac arteries from adult spontaneously hypertensive rats were studied with isometric tension recording. After ensuring the function integrity of the arteries, concentration-response curves to addition of Ang I (10−9-10−6 M) were performed after 30 min incubation with MIX (50:50 mixture of BSG:BSY) or BSG (0.86 mg/mL), or captopril (an ACE-inhibitory drug) or Krebs solution. ResultsMIX peptides (without simulated oral administration) enhanced Ang I-induced vasoconstriction, but lacked vascular effects after simulated oral administration. By contrast, BSG peptides (without simulated oral administration) did not exhibit vascular effects, whereas they promoted a marked decrease in vasocontraction evoked by the generated Ang II after simulation of the oral route, implying their capability to inhibit ACE. Additionally, to elucidate this inhibitory mechanism, Michaelis-Menten and Lineweaver-Burk plots indicated a mixed inhibition type. ConclusionWith simulation of the oral route, BSG peptides were able to inhibit vascular ACE with a similar efficacy as the antihypertensive drug captopril, suggesting the potential to mitigate the burden of hypertension.

Effect of Calamintha officinalis on Vascular Contractility and Angiotensinconverting Enzyme-2.

The study aimed to assess the antihypertensive activity of Calamintha officinalis. Calamintha officinalis (CO) is a medicinal and aromatic herb as well as an antihypertensive plant that is widely used for its medicinal properties in several regions. This study aimed to evaluate the effect of the aqueous extract of Calamintha officinalis (AECO) on vasorelaxant activity and arterial blood pressure under normal and hypertensive states in rats. Additionally, the effect of AECO on vascular angiotensin-converting enzyme 2 (ACE-2) was assessed. In the current study, AECO (100 mg/Kg) was prepared, and its antihypertensive ability was assessed in L-NG-Nitro arginine methyl ester (L-NAME)-induced hypertensive rats. Blood pressure and heart rate were recorded for 6 h for the acute experiment and during seven days for the subchronic treatment. The results indicated that AECO reduced the systolic, diastolic, and mean arterial blood pressure in hypertensive rats. In addition, the study showed that AECO exerts a vasorelaxant ability through the sGC-cGMP induction pathway, vascular cyclooxygenase pathway, and the opening of K+ channels. However, AECO had no inhibitory effect on aortic ACE-2. The study illustrates the beneficial action of AECO as an antihypertensive and vasorelaxant agent.

Vitamin C Inhibits Angiotensin-Converting Enzyme-2 in Isolated Rat Aortic Ring.

The study aimed to assess the inhibitory effect of Vitamin C on angiotensin-converting enzyme 2. Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which uses angiotensin-converting enzyme 2 (ACE-II) as the first route to infect human cells. Accordingly, agents with potential inhibition of ACE-II receptors might be effective in the prevention and management of COVID-19. The goal of this work was to assess the possible inhibitory effect of ACE-II on ascorbic acid using an ex vivo approach based on the inhibition of diminazene-induced vasorelaxation. In the present study, diminazene was used as a known specific inhibitor of ACE-II. Then, the vasorelaxant effect of ascorbic acid on diminazene-induced relaxation was examined using isolated aortic rings. All experiments of this study were evaluated on isolated aortic rings precontracted by epinephrine. The results confirmed that diminazene-induced vasorelaxation in a dose-dependent manner. More interestingly, ascorbic acid inhibited diminazene-induced vasorelaxation in a dose-dependent manner. This investigation provides valuable experimental proof of the efficacy of ascorbic acid (Vitamin C) on inhibiting ex vivo vascular angiotensin-converting enzyme II, which is known among the pharmacological targets of anti-COVID-19 drugs.

Syzygium gratum Extract Alleviates Vascular Alterations in Hypertensive Rats.

Background and Objectives: Syzygium gratum (SG) is a local vegetable and widely consumed in Thailand. Previously, a strong antioxidative effect of SG extract has been reported. The effects of SG extract on hypertension have remained unknown. The effect of SG aqueous extract on blood pressure and vascular changes were examined in L-NAME-induced hypertensive rats (LHR), and its potential active constituents were also explored. Materials and Methods: Male Sprague Dawley rats were allocated to control, L-NAME (40 mg/kg/day), L-NAME + SG (100, 300, 500 mg/kg/day), or captopril (5 mg/kg/day) groups. The components of SG extract were analyzed. Results: The analysis of aqueous SG extract was carried out using HPLC-Mass spectroscopy, and phenolic compounds could be identified as predominant components which might be responsible for its antihypertensive effects observed in the LHR model (p < 0.05). Additionally, SG extract also improved vascular responses to acetylcholine and decreased vascular remodeling in LHR (p < 0.05). Enhancements of eNOS expression and plasma nitric oxide metabolite levels, and attenuation of angiotensin converting enzyme (ACE) activity and plasma angiotensin II levels were observed in the LHR group treated with SG. Moreover, SG exhibited strong antioxidant activities by reducing vascular superoxide generation and systemic malondialdehyde in LHRs. Captopril suppressed high blood pressure and alleviated vascular changes and ACE activity in LHRs, similar to those of the SG extract (p < 0.05). Conclusion: Our results suggest that the SG extract exhibited antihypertensive effects, which is relevant to alleviation of vascular dysfunction and vascular remodeling of LHRs. These effects might be mediated by phenolic compounds to inhibit ACE activity and scavenge reactive oxygen species in LHR.

Vascular dysfunction and remodeling associated with 20‐HETE‐dependent hypertension is prevented in 20‐HETE receptor (GPR75) null mice

The potent vasoactive lipid 20‐Hydroxyeicosatetraenoic acid (20‐HETE) exhibits a range of bioactions across the vasculature including stimulation of endothelial dysfunction (ED) and increases in smooth muscle contractility; all of which promote hypertension. We have recently identified the G‐protein coupled receptor 75 (GPR75) as the receptor to which 20‐HETE binds and triggers signaling pathways culminating with the aforementioned effects. Previous studies have clearly shown the Cyp4a12tg mouse to be an animal model for the study of 20‐HETE and phenotypes associated with 20‐HETE‐dependent hypertension. In this model, expression of the 20‐HETE synthase, Cyp4a12, is under the control of a tetracycline (doxycycline, DOX) promoter and treatment of Cyp4a12tg (Gpr75+/+4a12tg) mice with DOX elicits increases circulating 20‐HETE levels followed by the promotion of pro‐hypertensive signaling including decreases in nitric oxide (NO) production and increases in vascular angiotensin converting enzyme (ACE) resulting in elevations in blood pressure (BP) (136 ± 4 vs. 103 ± 4 mmHg; P &lt; 0.05). In this study, we examined whether the deletion of GPR75 affects the onset and progression of hypertension and vascular remodeling in the Cyp4a12tg mice by crossing Gpr75−/− with Cyp4a12tg mice. Gpr75−/− 4a12tg treated with DOX chow for 42 days did not exhibit any changes in BP (103 ± 4 vs. 100 ± 6 mmHg). 20‐HETE‐mediated increases in BP in DOX‐treated Cyp4a12tg mice are associated with ED as indicated by reduced relaxation response to acetylcholine (ACh). Wire myography of renal interlobar arteries from DOX‐treated Gpr75+/+4a12tg mice pre‐constricted with phenylephrine exhibited a diminished relaxation response to ACh compared to mice receiving regular chow (44 ± 4% vs. 91 ± 2% relaxation; P &lt; 0.05). In contrast, ACh‐induced relaxations in arteries from DOX‐treated Gpr75−/− 4a12tg mice were not impaired and responded similarly to ACh as vessels from vehicle‐treated Gpr75−/− 4a12tg mice (89 ± 1% vs. 89 ± 2% relaxation; P &lt; 0.05). Another hallmark of persistent elevations in BP over time and 20‐HETE‐dependent hypertension is the development of dynamic vascular remodeling with increases in media thickness (MT), media‐to‐lumen ratio (M:L) and cross sectional area (CSA). Gpr75+/+4a12tg mice receiving DOX for 42 days exhibit an increase in remodeling of renal resistance arteries as indicated by elevations in MT (24 ± 1 vs. 12 ± 1 μm), M:L (0.29 ± 0.02 vs. 0.12 ± 0.01) and CSA (15 ± 1 vs. 8 ± 1 μm2 × 103) compared to Gpr75+/+4a12tg mice receiving regular chow. In contrast, DOX treated Gpr75−/− 4a12tg mice, as opposed to vehicle‐treated Gpr75−/− 4a12tg mice, did not display any changes to MT (12 ± 1 vs. 11 ± 1 μm), M:L (0.13 ± 0.01 vs. 0.11 ± 0.01 ) or CSA (8± 1 vs. 7 ± 0.3 μm2 × 103). Taken together, this data support the hypothesis that 20‐HETE required its receptor, GPR75, in order to drive pro‐hypertensive signaling that promotes endothelial dysfunction, vascular remodeling and hypertension.Support or Funding InformationSupported by NIH grants HL39793 (MLS), HL39793‐01S1 (VG) and by the Intramural Research Program of the NIH (Z01 ES025034 (DCZ)).

MiR155-5p in adventitial fibroblasts-derived extracellular vesicles inhibits vascular smooth muscle cell proliferation via suppressing angiotensin-converting enzyme expression

ABSTRACT Proliferation of vascular smooth muscle cells (VSMCs) plays crucial roles in vascular remodelling and stiffening in hypertension. Vascular adventitial fibroblasts are a key regulator of vascular wall function and structure. This study is designed to investigate the roles of adventitial fibroblasts-derived extracellular vesicles (EVs) in VSMC proliferation and vascular remodelling in normotensive Wistar-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR), an animal model of human essential hypertension. EVs were isolated from aortic adventitial fibroblasts of WKY (WKY-EVs) and SHR (SHR-EVs). Compared with WKY-EVs, miR155-5p content was reduced, while angiotensin-converting enzyme (ACE) content was increased in SHR-EVs. WKY-EVs inhibited VSMC proliferation of SHR, which was prevented by miR155-5p inhibitor. SHR-EVs promoted VSMC proliferation of both strains, which was enhanced by miR155-5p inhibitor, but abolished by captopril or losartan. Dual luciferase reporter assay showed that ACE was a target gene of miR155-5p. MiR155-5p mimic or overexpression inhibited VSMC proliferation and ACE upregulation of SHR. WKY-EVs reduced ACE mRNA and protein expressions while SHR-EVs only increased ACE protein level in VSMCs of both strains. However, the SHR-EVs-derived from the ACE knockdown-treated adventitial fibroblasts lost the roles in promoting VSMC proliferation and ACE upregulation. Systemic miR155-5p overexpression reduced vascular ACE, angiotensin II and proliferating cell nuclear antigen levels, and attenuated hypertension and vascular remodelling in SHR. Repetitive intravenous injection of SHR-EVs increased blood pressure and vascular ACE contents, and promoted vascular remodelling in both strains, while WKY-EVs reduced vascular ACE contents and attenuated hypertension and vascular remodelling in SHR. We concluded that WKY-EVs-mediated miR155-5p transfer attenuates VSMC proliferation and vascular remodelling in SHR via suppressing ACE expression, while SHR-EVs-mediated ACE transfer promotes VSMC proliferation and vascular remodelling.

Effect of Huangdi Anxiao Capsules on zebrafish vascular lesions induced by high glucose and high fat

Zebrafish of different strains with 5 dpf (5 days post-fertilization) were selected and fed with 0.2% high-fat diet for 8 h and 3% glucose solution for 16 halternatively during the day and night for 4 consecutive days. The zebrafish model was established and randomly divided into model group, Huangdi Anxiao Capsules (260 mg·L⁻¹) group and pioglitazone (32 mg·L⁻¹) group. The drug treatment groups were given the water-soluble drugs, with a volume of 25 mL, and incubated in a 28 °C incubator for 4 days. To detect the exposure to the corresponding drugs, the normal control group was set up. Thirty zebrafish were included in each group. The effect of Huangdi Anxiao Capsules on vascular wall thickness, fluorescence intensity of islet beta cells, fluorescence intensity of macrophages, and blood flow velocity of zebrafish were detected. The expressions of vascular endothelial growth factor (vegfaa) and angiotensin converting enzyme (ACE) were detected by RT-PCR. The results showed that compared with the model group, Huangdi Anxiao Capsules can significantly reduce the thickness of the blood vessel wall, increase the fluorescence intensity of islet β cells and macrophages, increase the blood flow velocity in vivo, and decrease the ACE and vegfaa expressions in zebrafish. It is suggested that Huangdi Anxiao Capsules may alleviate zebrafish vascular lesions by regulating the expressions of ACE and vegfaa.

Modulation of Vascular ACE by Oxidative Stress in Young Syrian Cardiomyopathic Hamsters: Therapeutic Implications.

Increased vascular angiotensin-converting enzyme (ACE) activity and oxidative stress are present in young Syrian cardiomyopathic hamsters (SCH) before the clinical manifestation of heart failure (HF). The developmental time-course of these alterations and their potential interactions, however, are still unknown. We evaluated mRNA and protein levels of ACE, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) in the vasculature of SCH from one to four months of age. Total RNA and proteins were quantified with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively. The role of nitric oxide (NO) on vascular ACE activity was also assessed. ACE mRNA and protein levels were up-regulated in SCH at two months of age compared with controls (CT) (p < 0.05). At this two-month stage, eNOS protein levels were lower in SCH (87%) than in CT (100%) (p < 0.05), although iNOS protein levels increased significantly (482%) compared to CT (100%; p < 0.05). In addition, ACE mRNA expression and activity were modulated by NO at two months of age. Thus, the combination of low eNOS and high iNOS protein levels may underlie vascular renin-angiotensin system (RAS) over-activation. Altogether, these factors may contribute to the development of endothelial dysfunction and vascular hyper-reactivity in the early stages of heart failure, and eventually trigger cardiac deterioration in this animal model of HF.

Risk factors of edema around the hematoma in hypertensive cerebral hemorrhage

Objective To investigate the risk factors of cerebral hemorrhage in hypertensive intracerebral hemorrhage, and to provide a reference for clinical treatment. Methods The clinical data of 118 patients with hypertensive cerebral hemorrhage treated in our hospital were analyzed retrospectively. The clinical data of patients was collected and statistical analysis was carried out, and the risk factors of edema around the hematoma were analyzed by Logistic regression analysis. Results Multivariate non conditional logistic regression analysis showed that, the course of hypertensive cerebral hemorrhage of edema around the hematoma was the risk factor, the longer the duration,the more risk of hypertensive cerebral hemorrhage edema around the hematoma enlargement. There was no significant correlation between sex,age,bleeding site,broken into ventricles and the edema around the hematoma in hypertensive intracerebral hemorrhage. Diastolic blood pressure was a risk factor for the edema around the hematoma in hypertensive cerebral hemorrhage, the diastolic blood pressure control was not good, and the swelling of the edema around the hematoma was increasing.While the systolic blood pressure,pulse pressure difference and hypertensive cerebral hemorrhage hematoma around the hematoma showed no obvious correlation. Use of amlodipine and vascular tension angiotensin converting enzyme inhibitor in hypertensive cerebral hemorrhage were the protective factors of edema around the hematoma, early application of amlodipine, vascular and nervous angiotensin converting enzyme inhibitor to control blood pressure helped to reduce hypertensive cerebral hemorrhage edema around the hematoma volume. Conclusion Amlodipine and vascular tension angiotensin converting enzyme inhibitors help to reduce hypertensive cerebral hemorrhage edema around the hematoma volume, while long course, poor control of diastolic blood pressure can promote hypertension cerebral hemorrhage edema around the hematoma volume increase. We should pay attention to the development of hypertensive cerebral hemorrhage and the control of diastolic blood pressure, as soon as possible to stabilize the patient's condition and avoid the expansion of the volume of edema around the hematoma. Key words: Hypertension; Cerebral hemorrhage; Edema around hematoma; Risk factor

MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin-converting enzyme 2–angiotensin-(1-7)–MAS axis functionality

AT1 antagonists effectively prevent atherosclerosis since AT1 upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT1 antagonists, the cross-talk between angiotensin-converting enzyme-angiotensin II-AT1 and angiotensin-converting enzyme 2–angiotensin-(1-7)–MAS axes suggests other mechanisms beyond AT1 blockage in such effects. For instance, angiotensin-converting enzyme 2 activity is inhibited by reactive oxygen species derived from AT1-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT1 antagonists could result from their inhibitory effects on the AT1-mediated negative modulation of vascular angiotensin-converting enzyme 2–angiotensin-(1-7)–MAS axis functionality. Interestingly, our results showed that early atherosclerosis triggered in thoracic aorta from high cholesterol fed-Apolipoprotein E-deficient mice impairs angiotensin-converting enzyme 2–angiotensin-(1-7)–MAS axis functionality by a proinflammatory-redox AT1-mediated pathway. In such mechanism, AT1 activation leads to the aortic release of tumor necrosis factor-α, which stimulates NAD(P)H oxidase/Nox1-driven generation of superoxide and hydrogen peroxide. While hydrogen peroxide inhibits angiotensin-converting enzyme 2 activity, superoxide impairs MAS functionality. Candesartan treatment restored the functionality of angiotensin-converting enzyme 2–angiotensin-(1-7)–MAS axis by inhibiting the proinflammatory-redox AT1-mediated mechanism. Candesartan also promoted vasoprotective and atheroprotective effects that were mediated by MAS since A779 (MAS antagonist) co-treatment inhibited them. The role of MAS receptors as the final mediators of the vasoprotective and atheroprotective effects of candesartan was supported by the vascular actions of angiotensin-(1-7) upon the recovery of the functionality of vascular angiotensin-converting enzyme 2–angiotensin-(1-7)–MAS axis.

Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension.

Increased vascular 20-HETE is associated with hypertension and activation of the renin-angiotensin system (RAS) through induction of vascular angiotensin-converting enzyme (ACE) expression. Cyp4a12tg mice, whose Cyp4a12-20-HETE synthase expression is under the control of a tetracycline (doxycycline, DOX) promoter, were used to assess the contribution of ACE/RAS to microvascular remodeling in 20-HETE-dependent hypertension. Treatment of Cyp4a12tg mice with DOX increased systolic blood pressure (SBP; 136 ± 2 vs. 102 ± 1 mmHg; P < 0.05), and this increase was prevented by administration of 20-HEDGE, lisinopril, or losartan. DOX-induced hypertension was associated with microvascular dysfunction and remodeling of preglomerular microvessels, which was prevented by 20-HEDGE, a 20-HETE antagonist, yet only lessened, but not prevented, by lisinopril or losartan. In ACE 3/3 mice, which lack vascular endothelial ACE, administration of 5α-dihydrotestosterone (DHT), a known inducer of 20-HETE production, increased SBP; however, the increase was about 50% of that in wild-type (WT) mice (151 ± 1 vs. 126 ± 1 mmHg). Losartan and 20-HEDGE prevented the DHT-induced increase in SBP in WT and ACE 3/3 mice. DHT treatment increased 20-HETE production and microvascular remodeling in WT and ACE 3/3 mice; however, remodeling was attenuated in the ACE 3/3 mice as opposed to WT mice (15.83 ± 1.11 vs. 22.17 ± 0.92 μm; P < 0.05). 20-HEDGE prevented microvascular remodeling in WT and ACE 3/3 mice, while losartan had no effect on microvascular remodeling in ACE 3/3. Taken together, these results suggest that RAS contributes to 20-HETE-mediated microvascular remodeling in hypertension and that 20-HETE-driven microvascular remodeling independent of blood pressure elevation does not fully rely on ACE activity in the vascular endothelium.

20‐SOLA, a Novel Water Soluble 20‐HETE Antagonist, Reduces Blood Pressure Through Regulation of Vascular ACE Expression via an IKK Dependent Pathway

Increased vascular 20‐HETE has been associated with hypertension and activation of the renin‐angiotensin system through induction of vascular angiotensin converting enzyme (ACE) expression. CYP4a14 knockout (KO) mice exhibit male‐specific androgen‐sensitive 20‐HETE‐dependent hypertension. A novel water‐soluble 20‐HETE antagonist, 2,5,8,11,14,17‐hexaoxanonadecan‐19‐yl 20‐hydroxyeicosa‐6(Z),15(Z)‐dienoate (20‐SOLA) was administered to CYP4a14 KO male and female mice (10mg/kg/day in drinking water). 20‐SOLA normalized blood pressure in hypertensive CYP4a14 KO male mice over the course of 10 days (124±1 vs 153 ±2 mmHg in untreated littermates) and had no effect on blood pressure of CYP4a14 KO female mice (126±1 vs 124±1 mmHg). Renal preglomerular microvessel (PGMV) ACE expression was significantly elevated in CYP4a14 KO males (3.57 ± 0.6 fold) compared to normotensive female mice and treatment with 20‐SOLA normalized vascular ACE expression. 20‐HETE‐mediated induction of vascular endothelial ACE expression has been demonstrated to be IKK‐dependent. PGMV of CYP4a14 KO male mice expressed a 2.6‐fold increase in phospho‐IKK compared to female KO mice and this increase was significantly reduced by 20‐SOLA (2.6±0.2 vs. 1.3±0.3 fold, respectively). These results suggest that the water soluble 20‐HETE antagonist 20‐SOLA reduces blood pressure in the male CYP4a14 KO mice, at least in part, through regulation of vascular ACE expression.

Phosphate Binding Reduces Aortic Angiotensin-Converting Enzyme and Enhances Nitric Oxide Bioactivity in Experimental Renal Insufficiency

Background: Disturbed calcium-phosphorus metabolism is associated with increased kidney angiotensin-converting enzyme (ACE) in experimental chronic renal insufficiency (CRI). However, information about the effects of phosphate binding and loading on vascular ACE is lacking. Methods: Fifteen weeks after 5/6 nephrectomy (NX), rats were placed on a phosphate-binding (NX+Ca, 3.0% Ca), phosphate-loading (NX+Pi, 1.5% Pi), or control diet for 12 weeks (NX and sham). Results: Aortic ACE, blood pressure, plasma phosphate, and parathyroid hormone were increased in the NX and NX+Pi groups, but were reduced with phosphate binding. Endothelium-mediated relaxations of isolated mesenteric conduit artery rings to acetylcholine were impaired in the NX and NX+Pi groups, but did not differ from sham in NX+Ca rats. Experiments with nitric oxide (NO) synthase inhibition in vitro suggested that the NO-mediated component of acetylcholine response was lower in the NX and NX+Pi groups, but did not differ from sham in NX+Ca rats. In all NX groups, aortic endothelial NO synthase (eNOS) was reduced, while plasma and urine concentrations of NO metabolites were increased. Aortic nitrated proteins and calcification were increased in the NX and NX+Pi groups when compared with the NX+Ca and sham groups. Conclusion: Hypertension in the NX model of CRI was associated with reduced vasorelaxation, decreased eNOS, and increased ACE and nitrated proteins in the aorta. Phosphate binding with calcium carbonate enhanced vasorelaxation via endogenous NO and suppressed elevation of ACE and nitrated proteins, suggesting reduced vascular oxidative stress. Our findings support the view that correction of the calcium-phosphorus balance prevents CRI-induced vascular pathophysiology.

Role of the ACE ID and PPARG P12A Polymorphisms in Genetic Susceptibility of Diabetic Nephropathy in a South Indian Population

BackgroundDiabetic nephropathy (DN) is one of the life-threatening disorders characterized by persistent albuminuria, raised arterial blood pressure, a lowered glomerular filtration rate, and high risk of cardiovascular morbidity and mortality. The vascular genes ACE (Angiotensin-converting enzyme), and PPARG (peroxisome proliferator activated receptor gamma) are involved in alterations in vascular endothelium, and are suggested to play a role in the susceptibility of diabetic nephropathy.ObjectivesThe aim of our study was to find out the role of ACE ID and PPARG P12A polymorphisms in genetic susceptibility of diabetic nephropathy in south Indian population.Patients and MethodsA total of 54 cases with diabetic nephropathy and 67 control subjects with diabetes were enrolled for our study. DNA was isolated from peripheral blood leucocytes, and genotyped using PCR-electrophoresis (ACE ID) or PCR-RFLP (PPARG P12A) methods.ResultsACE ID genotypes followed Hardy-Weinberg equilibrium in both cases and controls. But P12A genotypes deviated from Hardy-Weinberg equilibrium in diabetic controls. Chi2 test was applied for the analysis of genotypic distributions in genotypic and dominant models. Odds ratios were also calculated. No significant differences in genotype frequencies of ACE ID and PPARG P12A polymorphisms were found on comparing patients with diabetic nephropathy with diabetic controls. The synergistic role of ACE ID* PPARG P12A interaction, did not show any association in patients with diabetic nephropathy when compared to diabetic controls.ConclusionsIn conclusion, the ACE and PPARG genes do not have a key role in conferring risk for diabetic nephropathy.

Benefits of delapril in hypertensive patients along the cardiovascular continuum

Angiotensin-converting enzyme inhibitors (ACEIs) are the first-line therapy for the treatment of hypertension. However, not all ACEIs are equal. Delapril is a nonsulfhydryl ACEI with unique properties. Delapril has a high lipophilicity and weak bradykinin potentiating action. As a result, delapril has a more potent inhibition capacity of vascular wall angiotensin-converting enzyme activity and a lower incidence of cough than enalapril or captopril. With regard to efficacy, delapril has a long-lasting antihypertensive effect with a trough/peak ratio that is in the upper range of different ACEIs and a positively high smoothness index. Thus, delapril effectively and smoothly reduces blood pressure over 24 h. Moreover, the benefits of delapril are not limited to hypertensive patients, but also in those with microalbuminuria, left ventricular hypertrophy, myocardial infarction or heart failure; delapril appears to be effective and well tolerated.

Powerful vascular protection by combining cilnidipine with valsartan in stroke-prone, spontaneously hypertensive rats

Cilnidipine is an L- and N-type calcium channel blocker (CCB), and amlodipine is an L-type CCB. Valsartan (10 mg kg−1), valsartan (10 mg kg−1) and amlodipine (1 mg kg−1), and valsartan (10 mg kg−1) and cilnidipine (1 mg kg−1) were administered once daily for 2 weeks to stroke-prone, spontaneously hypertensive rats (SHR-SPs). Blood pressure was significantly reduced by valsartan, and it was further reduced by the combination therapies. Vascular endothelial dysfunction was significantly attenuated in all therapeutic groups, and further significant attenuation was observed in the valsartan+cilnidipine-treated group, but not in the valsartan+amlodipine-treated group. Vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX1 gene expression was significantly attenuated in all therapeutic groups, and significantly greater attenuation was observed in the valsartan+cilnidipine-treated group than in the valsartan-treated group. Compared with the valsartan-treated group, the positive areas for 4-hydroxy-2-nonenal were significantly lower only in the valsartan+cilnidipine-treated group. Plasma renin activity was significantly augmented in the valsartan-treated group, and it was significantly attenuated in the valsartan+cilnidipine-treated group. A significant increase in the ratio of plasma angiotensin-(1-7) to angiotensin II was observed only in the valsartan+cilnidipine-treated group. Vascular angiotensin-converting enzyme (ACE) gene expression was significantly attenuated only in the valsartan+cilnidipine-treated group, but ACE2 gene expression was significantly higher in all of the therapeutic groups. Thus, valsartan and cilnidipine combination therapy might have a powerful protective effect in the vascular tissues via increases in the angiotensin-(1-7)/angiotensin II ratio in plasma.

TrACEing Angiotensin II Type 1 to Right Ventricular Hypertrophy

TrACEing Angiotensin II Type 1 to Right Ventricular Hypertrophy

Role of renin–angiotensin system and oxidative status on the maternal cardiovascular regulation in spontaneously hypertensive rats

The purpose of this study was to investigate the contribution of renin-angiotensin system (RAS) and oxidative status on the maternal cardiovascular regulation at the end of pregnancy in normotensive and spontaneously hypertensive rats (SHR). Blood pressure (BP), mesenteric arterial bed (MAB) reactivity, mesenteric oxidative damage, protein expression, and antioxidant activities were compared between four groups: SHR (SHR-P) and normotensive Wistar controls (W-P) in the 20th day of pregnancy or age-matched nonpregnant rats (SHR-NP and W-NP). BP in W-P and SHR-P was reduced at the end of pregnancy. The vasodilator effects of angiotensin II (Ang II) and angiotensin 1-7 (Ang-(1-7)) were higher in SHR-P than in other groups. Endothelial nitric oxide synthase (eNOS) expression was increased in W-P and SHR-P compared to nonpregnant groups. Angiotensin-converting enzyme (ACE) and AT(1) receptor expressions were increased in SHR-NP compared to normotensive groups and pregnancy reduced their expressions in SHR. No difference was observed in AT(2) receptor expression among the groups. ACE2 expression was higher in hypertensive than normotensive groups. The levels of thiobarbituric acid-reactive substances (TBARS) were reduced in pregnant compared to nonpregnant groups. Superoxide dismutase (SOD) activity was reduced in SHR-P compared to SHR-NP. However, pregnancy increased catalase (CAT) and glutathione peroxidase (GPx) activities in normotensive rats and SHR, respectively. The results suggest that the reduction of BP to normal values at the end of pregnancy in SHR may be related to an increased NO production and vasorelaxation to Ang II and Ang-(1-7) associated with decreased expression of vascular ACE and AT(1) receptors and oxidative status.

Regional variation in angiotensin converting enzyme activity in the human placenta

Sensitivity of chorionic plate arteries to angiotensin II (AngII) is greatest at the placental periphery. Angiotensin converting enzyme (ACE) is central to the synthesis of AngII and is present in the placental vasculature. We measured vascular ACE activity/mg protein at 8-9 sites between the cord insertion and the periphery in 12 term placentae from normotensive, vaginally-delivered women. ACE increased from insertion to the periphery (P = 0.015); median ACE for each placenta was positively correlated with placental weight (P < 0.05) and placental:birthweight ratio (P < 0.02). We speculate that this may be related to fetal programming since placental:birthweight ratio is related to long-term health.

CYP4A2-Induced Hypertension Is 20-Hydroxyeicosatetraenoic Acid– and Angiotensin II–Dependent

We have shown previously that increased vascular endothelial expression of CYP4A2 leads to 20-hydroxyeicosatetraenoic (20-HETE)-dependent hypertension. The renin-angiotensin system is a key regulator of blood pressure. In this study, we examined possible interactions between 20-HETE and the renin-angiotensin system. In normotensive (110±3 mm Hg) Sprague-Dawley rats transduced with a lentivirus expressing the CYP4A2 cDNA under the control of an endothelial-specific promoter (VECAD-4A2), systolic blood pressure increased rapidly, reaching 139±1, 145±3, and 150±2 mm Hg at 3, 5, and 10 days after transduction; blood pressure remained elevated, thereafter, with maximum levels of 163±3 mm Hg. Treatment with lisinopril, losartan, or the 20-HETE antagonist 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid decreased blood pressure to control values, but blood pressure returned to its high levels after cessation of treatment. Endothelial-specific overexpression of CYP4A2 resulted in increased expression of vascular angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor and increased levels of plasma and tissue angiotensin II; all were attenuated by treatment with HET0016, an inhibitor of 20-HETE synthesis, or with 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid. In cultured endothelial cells, 20-HETE specifically and potently induced ACE expression without altering the expression of ACE2, angiotensinogen, or angiotensin II receptors. This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and angiotensin II type 1 receptor expression and increases angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of the renin-angiotensin system that is likely initiated at the level of ACE induction.