Inhibition of Neointima by Angiotensin-Converting Enzyme Inhibitor in Porcine Coronary Artery Balloon-Injury Model

Abstract

Abstract-Because hepatocyte growth factor (HGF) stimulates growth of endothelial cells exclusively without replication of vascular smooth muscle cells, we hypothesized that HGF may play a role in cardiovascular disease. In human vascular smooth muscle cells, angiotensin II suppressed local vascular HGF production in a dose-dependent manner. Using a rat balloon-injury carotid artery model, we demonstrated that blockade of angiotensin II inhibited neointimal formation, accompanied by a significant increase in local HGF production. However, the relation of vascular HGF to endothelial function was not clarified. Moreover, it is important to test the hypothesis in animal models that are more similar to human restenosis. Thus, in the present study, we used a porcine coronary artery balloon-injury model to study the role of angiotensin II in regulation of the local HGF system in vivo. Expression of HGF mRNA was significantly decreased in balloon-injured coronary arteries versus intact vessels. An angiotensin-converting enzyme (ACE) inhibitor (perindopril) significantly inhibited neointimal formation after balloon injury compared with vehicle (PϽ0.05). In addition, vasodilator response of balloon-injured coronary arteries to bradykinin was restored by perindopril treatment, whereas no vasodilator response was observed in balloon-injured vessels treated with vehicle. Vasodilator response of balloon-injured arteries induced by perindopril was completely abolished by N w -nitro-L-arginine methyl ester. Of particular interest, vascular HGF mRNA was significantly increased in balloon-injured vessels treated with perindopril as compared with vehicle. Overall, the present study demonstrated that ACE inhibitor significantly inhibited neointimal formation, accompanied by significant improvement of endothelial dysfunction and a significant increase in local vascular HGF mRNA in vivo in a porcine coronary artery balloon-injury model. Given the strong mitogenic activity of HGF on endothelial cells, improvement of endothelial dysfunction by perindopril might be due to increased local HGF expression through enhancement of reendothelialization after balloon injury, in addition to its direct effect, ACE inhibition. Downregulation of the local vascular HGF system may play an important role in the pathogenesis of cardiovascular disease. From this viewpoint, we previously reported that hepatocyte growth factor (HGF) has the unique characteristic of stimulating endothelial cell growth exclusively without stimulating VSMC growth, 3,4 although HGF is well known to be a mesenchyme-derived pleiotropic factor that regulates cell growth and motility and morphogenesis of various types of cells. 5,6 Moreover, the presence of HGF and its specific receptor, c-met, has been detected in vascular tissues. 7 Our previous reports documented that angiotensin (Ang) II significantly inhibited local HGF production through transforming growth factor (TGF)-␤ activation and a non-TGF-␤ pathway. 8,9 In addition, an angiotensin-converting enzyme (ACE) inhibitor o...

Secondary Prevention of Coronary Disease with ACE Inhibition-does Blood Pressure Reduction with Perindopril Explain the Benefits in EUROPA?

“…This may also explain the differences in outcome in secondary prevention of CAD between different ACE inhibitors [23] Bradykinin, by increasing cNOS expression, improves endothelial dysfunction, has anti-oxidant effects, enhances fibrinolysis, and reduces cardiovascular remodelling, as such counteracting the effects of angiotensin II. In animal experimental models, perindopril prevents atherosclerosis [24] and reduces intima proliferation [25,26]. In patients with hypertension, it improves endothelial dysfunction and increases t-PA release [27][28][29].…”

Inhibition of NFκB activation using cis-element ‘decoy’ of NFκB binding site reduces neointimal formation in porcine balloon-injured coronary artery model

“…The femoral artery was surgically exposed, and a cannula was introduced into the orifice of the left coronary artery over a guide wire. 31 Before insertion of the catheter, heparin (5000 IU) was intravenously injected. A balloon catheter (length 2 cm; balloon size 2.5 or 3.0 mm; Boston Scientific Com., MA, USA) was placed in the left ascending coronary artery over the guide wire under angiographic guidance.…”

Molecular strategy using cis-element ‘decoy’ of E2F binding site inhibits neointimal formation in porcine balloon-injured coronary artery model

“…Optimal resting tension was determined in baseline studies, and the response to vasoactive drugs was then determined. 30 Cumulative dose-response curves to KCl (1 to 100 mM) were established. The vessels were then submaximally precontracted with KCl (typically 50 mM), and endothelial function was evaluated by determining vascular relaxation to bradykinin (10 -8 to 10 -4 M) in the presence of indomethacin (3 × 10 -6 M).…”