Angiotensin-converting Enzyme Inhibition Delays Pulmonary Vascular Neointimal Formation

Abstract

Primary pulmonary hypertension (PPH) is a disease characterized pathologically by pulmonary artery medial hypertrophy, adventitial thickening, and neointimal proliferation. Increasing recognition of the importance of remodeling to the pathogenesis of PPH suggests new therapeutic possibilities, but it will be necessary to (1) identify essential mediators of remodeling, and (2) demonstrate that inhibiting those mediators suppresses remodeling before new antiremodeling therapies can be considered feasible. The effect of angiotensin-converting enzyme (ACE) inhibition on pulmonary vascular remodeling was studied in a newly developed rat model in which neointimal lesions develop between 3 and 5 wk after monocrotaline injury is coupled with increased pulmonary artery blood flow after contralateral pneumonectomy. Neointimal formation was significantly suppressed at 5 wk by ACE inhibition whether it was started 10 d before or 3 wk after remodeling was initiated, although medial hypertrophy and adventitial thickening still developed. By 11 wk, the extent of neointimal formation in rats treated with ACE inhibition was similar to rats without ACE inhibition at 5 wk. Pulmonary artery pressures and right ventricular weights correlated with the extent of neointimal formation. Northern blot analysis and in situ hybridization demonstrated marked suppression of lung tropoelastin and type I procollagen gene expression in the presence of ACE inhibition. An angiotensin II type I receptor antagonist partially, but not completely, replicated the effects of ACE inhibition. These data suggest that the tissue angiotensin system may be a target for therapeutic efforts to suppress the vascular remodeling that is characteristic of primary pulmonary hypertension.

Myocyte Morphological Characteristics Differ Between the Phases of Pulmonary Hypertension-Induced Ventricular Hypertrophy and Failure

“…The death rate from failing myocardium in the right ventricle as a result of MCT administration increases in a dose-dependent manner. [12][13][14][15][16][17] Hirota, et al 2) subcutaneously injected 40 mg/kg of MCT solution into rats. Two weeks later, the right ventricular systolic pressure rose to 25.4 ± 2.2 mmHg in the MCT group and to 13.3 ± 1.4 mmHg in the control group.…”

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

“…19 Increased angiotensin-converting enzyme expression is observed in plexiform lesions in PAH, 20 and angiotensin-converting enzyme inhibition seems to delay pulmonary vascular neointimal formation. 21 Therefore, the renin-angiotensinaldosterone system (RAAS) represents a group of candidate genes that could modify disease severity and/or age at diagnosis of individuals predisposed to develop PAH. Angiotensin II (Ang II) binds primarily to the Ang II type-1 receptor (AT1R) to promote vascular smooth muscle constriction.…”

Role of Chymase-Dependent Angiotensin II Formation in Monocrotaline-Induced Pulmonary Hypertensive Rats

“…Previous investigators have reported that lung ACE activities were significantly decreased in monocrotaline-induced PH rats and have suggested that the reduction in lung ACE activity is a result rather than a cause of PH (25). However, ACE inhibitors have been shown to prevent monocrotaline-induced PH in rats (26,27), while the effects of ARBs in monocrotaline-induced PH rats have not yet been determined. Cassiss et al (28) reported that the ARB losartan failed to prevent monocrotaline-induced PH.…”

“…Okada et al (26) compared an ACE inhibitor, quinapril, with losartan, and though both agents were found to prevent PH, the extent of inhibition with losartan was clearly weaker than with quinapril. From these results, they speculated that the mechanism of action of ACE inhibitors in PH might depend on the increase of bradykinin rather than on the reduction of angiotensin II formation (26,28). On the other hand, the ARB irbesartan was found to significantly prevent PH (29), just as our study showed that candesartan prevented PH.…”