Overexpression of ACE2 Enhances Plaque Stability in a Rabbit Model of Atherosclerosis

Abstract

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...

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

“…Our results revealed that rats in the no treatment group developed severe hyperglycemia, albuminuria and renal pathological changes as well as enhanced Ccr, which are characteristic of early diabetic nephropathy, and demonstrated that an animal model of diabetic nephropathy was successfully established. In our previous study (8) and the current study, the high expression of GFP in the Ad-GFP group and the high expression and activity of ACE2 in the Ad-ACE2 group, as well as the lack of noticeable side effects in these groups, indicated a high efficiency and safety of ACE2 gene transfer.…”

“…Recombinant adenoviruses (Ad) carrying the murine ACE2 (Ad-ACE2) or a control transgene EGFP (Ad-EGFP) were prepared with the AdMax system (Microbix Biosystems) using our previously described method (8).…”

“…Recently, the role of ACE2 in the modulation of cardiovascular function has been investigated by deliberate genetic manipulation, including targeted disruption (5,6) and overexpression (7)(8)(9), and these studies have consistently demonstrated that ACE2 has beneficial effects of antihypertension, antifibrosis and antiatherosclerosis. Thus, ACE2 may provide a new therapeutic target for the treatment of cardiovascular diseases.…”

ACE2 Activation Promotes Antithrombotic Activity

“…The role of ACE2 in the pathophysiology of cardiovascular diseases is currently under intense investigation. The involvement of this enzyme in cardiac contractile function, hypertension, atherosclerosis and other cardiovascular diseases has recently been demonstrated (15)(16)(17). The present study offers evidence that ACE2 is involved in the hemostatic process and exhibits a protective action against thrombosis.…”

Combination of fluvastatin and losartan relieves atherosclerosis and macrophage infiltration in atherosclerotic plaques in rabbits

“…Recent studies have shown that the combination of an HMGCoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor and an ARB has a better effect on relieving the severity of atherosclerosis and down-regulating the expression of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) than the use of a single drug [6] . Our previous study showed that angiotensin II plays an important role in the pathogenesis Combination of fluvastatin and losartan relieves atherosclerosis and macrophage infiltration in athero sclerotic plaques in rabbits 1260 www.nature.com/aps Yang YP et al Acta Pharmacologica Sinica npg of atherosclerosis [7,8] . In addition, Han et al and Koh et al also demonstrated that the combination of simvastatin and losartan has vascular protective effects [9,10] .…”