BACKGROUNDSalt substitutes with reduced sodium levels and increased potassium levels have been shown to lower blood pressure, but their effects on cardiovascular and safety outcomes are uncertain. METHODSWe conducted an open-label, cluster-randomized trial involving persons from 600 villages in rural China. The participants had a history of stroke or were 60 years of age or older and had high blood pressure. The villages were randomly assigned in a 1:1 ratio to the intervention group, in which the participants used a salt substitute (75% sodium chloride and 25% potassium chloride by mass), or to the control group, in which the participants continued to use regular salt (100% sodium chloride). The primary outcome was stroke, the secondary outcomes were major adverse cardiovascular events and death from any cause, and the safety outcome was clinical hyperkalemia. RESULTSA total of 20,995 persons were enrolled in the trial. The mean age of the participants was 65.4 years, and 49.5% were female, 72.6% had a history of stroke, and 88.4% a history of hypertension. The mean duration of follow-up was 4.74 years. The rate of stroke was lower with the salt substitute than with regular salt (29.14 events vs. 33.65 events per 1000 person-years; rate ratio, 0.86; 95% confidence interval [CI], 0.77 to 0.96; P = 0.006), as were the rates of major cardiovascular events (49.09 events vs. 56.29 events per 1000 person-years; rate ratio, 0.87; 95% CI, 0.80 to 0.94; P<0.001) and death (39.28 events vs. 44.61 events per 1000 person-years; rate ratio, 0.88; 95% CI, 0.82 to 0.95; P<0.001). The rate of serious adverse events attributed to hyperkalemia was not significantly higher with the salt substitute than with regular salt (3.35 events vs. 3.30 events per 1000 person-years; rate ratio, 1.04; 95% CI, 0.80 to 1.37; P = 0.76). CONCLUSIONSAmong persons who had a history of stroke or were 60 years of age or older and had high blood pressure, the rates of stroke, major cardiovascular events, and death from any cause were lower with the salt substitute than with regular salt.

Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated AngII-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERKp38, JAK-STAT, and AngII-ROS-NF-κB signaling pathways and upregulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis.atherosclerosis | endothelial cell | gene therapy | smooth muscle cell | signaling pathway A ccumulating evidence indicates that endothelial cell (EC) dysfunction and the proliferation and migration of vascular smooth muscle cells (VSMCs) are salient features of early atherosclerotic lesions, and that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of atherosclerosis (1, 2). Angiotensin II (AngII) promotes EC dysfunction and VSMC proliferation and migration by increasing the expression of monocyte chemoattractant protein 1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), leading to aggravation of atherosclerotic lesions (3-5). Delivery of ACE inhibitors or AngII type 1 receptor (AT 1 R) blockers to limit AngII bioactivity is an effective approach against atherosclerosis.Recent studies show that endogenous levels of AngII are regulated by the opposing action of two carboxypeptidases, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). The latter is thought to counterbalance ACE by cleaving AngI into the inactive angiotensin 1-9 and cleaving AngII into the vasodilating and antiproliferative angiotensin 1-7 [Ang(1-7)]. ACE2 is thus considered a potential therapeutic target of RAS for the treatment of cardiovascular diseases by virtue of its key role in the formation of vasoprotective peptides from AngII (6-8). Our recent study using a rabbit atherosclerosis model showed that ACE2 overexpression stabilized aortic plaques at a late stage and attenuated the progression of early atherosclerotic lesions. These ther...

Objective-The purpose of this study was to test the hypothesis that ACE2 overexpression may enhance atherosclerotic plaque stability by antagonizing ACE activity and converting angiotensin II to angiotensin 1-7. Methods and Results-Atherosclerotic plaques were induced in the abdominal aorta of 114 rabbits by endothelial injury and atherogenic diet. Gene therapy was performed in group A at week 4 and in group B at week 12, respectively. Each group of rabbits were randomly divided into 3 subgroups which received, respectively, a recombinant ACE2 expressing vector (AdACE2), a control vector AdEGFP and AdACE2ϩA779, an antagonist of angiotensin 1-7 receptor. Local ACE2 overexpression attenuated the progression of lesions from week 4 to week 8, but not progression of plaque size from week 12 to week 16. In group B rabbits, local ACE2 overexpression resulted in stable plaque compositions, ie, fewer macrophages, less lipid deposition and more collagen contents, higher plaque stability scores, decreased angiotensin II levels, and increased angiotensin 1-7 levels in plaque tissues in the AdACE2 subgroup compared with those in the AdEGFP subgroup. Conclusions-Overexpression of ACE2 results in stabilized atherosclerotic plaques and the mechanism is probably the conversion of vasoconstrictive angiotensin II to vessel protective angiotensin 1-7. (Arterioscler Thromb Vasc Biol. 2008;28:1270-1276)Key Words: atherosclerosis Ⅲ angiotensin converting enzyme 2 Ⅲ angiotensin Ⅲ inflammation Ⅲ plaque stability R ecent studies have shown that the endogenous levels of angiotensin II (Ang II) are regulated by the opposing action of 2 carboxypeptidases, angiotensin-converting enzyme (ACE) and ACE2. The latter is a more recently discovered homologue of ACE and is thought to counterbalance ACE by cleaving Ang I and Ang II into inactive Ang 1-9 and vasodilating and antiproliferative Ang-(1-7), respectively. ACE2 is thus considered a potential therapeutic target of the rennin-angiotensin system (RAS) for treatment of cardiovascular diseases owing to its key role in the formation of vessel protective peptides from Ang II. 1,2 Both ACE and ACE2 are considered key regulators of many cardiovascular pathological processes. Although Ang II and its receptor angiotensin subtype 1 receptor (AT 1 R) have been reported by many studies to be expressed in atherosclerotic lesions, ACE2 was reported only recently to be expressed in vascular endothelial cells, macrophages, and smooth muscle cells (SMCs). 3 More recently, ACE2 gene transfer was reported to result in a significant regression of left ventricular hypertrophy in spontaneously hypertensive rats. 4 However, little is known about the exact role of ACE2 in the formation and stabilization of atherosclerotic plaques. Because local RAS plays an important role in the pathogenesis of atherosclerosis, 5 it is reasonable to assume that imbalance of the activities of these 2 enzymes, ACE and ACE2, may have paramount importance in the pathogenesis of atherosclerosis. Therefore, we hypothesize that overexpress...

This study was carried out to test the hypothesis that Tongxinluo (TXL) as a Chinese herbal medicine enhances stability of vulnerable plaque dose dependently via lipid-lowering and anti-inflammation effects, similar to a high-dose simvastatin therapy. After abdominal aortic balloon injury, 75 rabbits were fed a 1% cholesterol diet for 10 wk and were then divided into five groups for 8-wk treatment: control group, low-dose TXL group, moderate-dose TXL group, high-dose TXL group, and high-dose simvastatin group. At the end of week 16, an adenovirus containing p53 was injected into the abdominal aortic plaques. Two weeks later, plaque rupture was induced by pharmacological triggering. The incidence of plaque rupture in all treatment groups (14.3%, 7.1%, 7.7%, and 7.1%) was significantly lower than that in control group (73.3%; P>0.01). TXL dose-dependently lowered serum lipid levels and inhibited systemic inflammation. Corrected acoustic intensity and fibrous cap thickness of the aortic plaques were significantly increased, whereas plaque area, plaque burden, vulnerable index, and expression of oxidized low-density lipoprotein (ox-LDL) receptor 1, matrix metalloproteinase 1 (MMP-1), MMP-3, tissue inhibitor of MMP 1, and NF-kappaB in plaques were markedly reduced in all treatment groups when compared with the control group. Similar to high-dose simvastatin group, high-dose TXL group exhibited a low serum level of low-density lipoprotein cholesterol and ox-LDL, a low expression level of systemic and local inflammatory factors and a low plaque vulnerability index, with no differences in the incidence of plaque rupture among all treatment groups. TXL dose-dependently enhances the stability of vulnerable plaques and prevents plaques from rupture. Simvastatin and TXL offer similar protection in terms of lipid-lowering, anti-inflammation, and antioxidation effects.

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The purpose of this study was to test the hypothesis that overexpression of angiotensin-converting enzyme 2 (ACE2) may favorably affect left ventricular (LV) remodeling and function after myocardial infarction (MI). The left anterior descending coronary artery was ligated to produce anterior MI in 100 Wistar-Kyoto rats that were randomly divided into Ad-ACE2, Ad-ACE2+A779, Ad-EGFP, model, and sham groups. Two weeks later, rats in the Ad-ACE2 and Ad-EGFP groups received direct intramyocardial injection of Ad-ACE2 and Ad-EGFP, respectively. Rats in the Ad-ACE2+A779 group received both intramyocardial injection of Ad-ACE2 and a continuous intravenous infusion of A779 for 15 days. LV volume and systolic function, the extent of myocardial fibrosis, and levels of ACE2, angiotensin II (Ang II), and collagen I protein expression were evaluated. Four weeks after ACE2 gene transfer, the Ad-ACE2 group showed reduced LV volume, extent of myocardial fibrosis, and expression levels of ACE, Ang II, and collagen I in the myocardium, and increased LV ejection fraction and levels of ACE2 activity and expression in comparison with the Ad-EGFP and model groups. These results suggest that ACE2 overexpression attenuated LV fibrosis and improved LV remodeling and systolic function. In conclusion, overexpression of ACE2 favorably affected the pathological process of LV remodeling after MI by inhibiting ACE activity, reducing AngII levels, and up-regulating Ang-(1-7) expression, thus providing a potential therapeutic target in the treatment of heart failure.

Background and purpose: Atherosclerotic plaque rupture and thrombosis are the main cause of acute coronary syndrome. The study was aimed to test the hypothesis that oral administration of rapamycin may attenuate inflammation, inhibit progression and enhance stability of atherosclerotic plaques. Experimental approach: Thirty New Zealand rabbits were subjected to balloon-induced endothelial injury of the abdominal aorta and were fed a diet of 1% cholesterol for 20 weeks. From week 9 to week 20, the animals were treated with oral rapamycin (0.5 mg·kg ; group B) and no drugs (group C). At the end of week 20, all rabbits were challenged with injection of Chinese Russell's viper venom and histamine. Serological, ultrasonographic, pathological, immunohistochemical and gene expression studies were performed. Key results: Rapamycin significantly increased the thickness of the fibrous caps and decreased plaque vulnerability index in group A rabbits. Serum lipid levels were higher whereas plaque burden was lower in group A than in group B (P < 0.05). The incidence of plaque rupture in group A (0%) and group B (0%) was significantly lower than that in group C (56.0%, P < 0.05). Conclusions and implications:Oral administration of rapamycin effectively attenuated inflammation, inhibited progression and enhanced stability of atherosclerotic plaques in rabbits, without altering serum lipid levels. Our findings suggest a novel approach to the treatment of atherosclerosis.

Objective-To test the hypothesis that chronic infusion of angiotensin-(1-7) [Ang-(1-7)] may dose-dependently inhibit atherosclerotic lesion formation by targeting vascular smooth muscle cells and a large dose of Ang-(1-7) may stabilize mature plaque by targeting macrophages. Approach and Results-In vivo, the effects of Ang-(1-7) on atherogenesis and plaque stability were observed in ApoE −/− mice fed a high-fat diet and chronic angiotensin II infusion. In vitro, the effects of Ang-(1-7) on vascular smooth muscle cells' proliferation and migration, and macrophage inflammatory cytokines were examined. Ang-(1-7) dosedependently attenuated early atherosclerotic lesions and inhibited vascular smooth muscle cells' proliferation and migration via suppressing extracellular regulated protein kinase/P38 mitogen-activated protein kinase and janus kinase/ signal transducers and activators of transcription activities and enhancing smooth muscle 22α and angiotensin II type 2 receptor expression. Ang-(1-7) treatment resulted in high contents of collagen and vascular smooth muscle cells, and low contents of macrophages and lipids in carotid mature plaques. Ang-(1-7) lowered the expression levels of proinflammatory cytokines and activities of matrix metalloproteinases in mature plaques. Conclusions-Ang-(1-7) treatment inhibits early atherosclerotic lesions and increases plaque stability in ApoE−/− mice, thus providing a novel and promising approach to the treatment of atherosclerosis. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Body Weight, Blood Pressure, and Serum Lipid ProfileAt the end of the first part (8 weeks) and the second part (10 weeks) of the in vivo study, both systolic and diastolic blood pressures were substantially increased in comparison with the baseline blood pressure measurements (data not shown). However, no significant differences were found in body weight, blood pressure, and serum lipid levels among vehicle-treated, Ang-(1-7)-treated and Ang-(1-7)+A779-treated groups, indicating that chronic infusion of Ang-(1-7) or A779 had no significant effects on these parameters (Table I in the online-only Data Supplement). In ApoE −/− mice without Ang-II infusion, blood pressure levels were not statistically different among vehicle-treated, Ang-(1-7)-treated, and Ang-(1-7)+A779-treated groups ( Figure 1; Table II in the online-only Data Supplement). Aortic Lesion FormationIn the first part of the in vivo study, the relative en face lesion area of the aorta arches was dose-dependently decreased in the Ang-(1-7)-treated subgroups. However, only the difference between the large dose of Ang-(1-7) subgroup and the vehicle-treated group reached a statistical significance. The antiatherosclerosis effect of Ang-(1-7) was significantly reversed by coadministration of A779 (Figure 2A and 2B). Similarly, the relative cross-sectional area of the aortic lesion also showed a dose-dependent decrease in the Ang-(1-7)-treated subgroups but only the difference between the large do...