Early Treatment with Fumagillin, an Inhibitor of Methionine Aminopeptidase-2, Prevents Pulmonary Hypertension in Monocrotaline-Injured Rats

Abstract

Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2) regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo , treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC) with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro . Platelet-derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients.

Structural and Mechanical Adaptations of Right Ventricle Free Wall Myocardium to Pressure Overload

“…Terminal invasive hemodynamics was performed on the normotensive (n=10) and hypertensive (n=10; noting that the same hypertensive rats were used in tissue-level biomechanical studies) rats to generate pressure-volume loops, from which relevant hemodynamic parameters were derived using methods described previously (38), (18). Ees was obtained by standard methods utilizing vena cava occlusion, e.g., (10,18,50).…”

A murine experimental model for the mechanical behaviour of viable right‐ventricular myocardium

“…The calculation of peak wall stress on the basis of Laplace's law provides an estimate of wall stress (Fung, 1993 b ). The calculations are based on a peak systolic pressure of 22 mmHg (Kass et al 2012), an RV outflow tract diameter of 2 mm, and a wall thickness of 0.6 mm. The results of this calculation were purely used for the purpose of establishing an initial experimental condition.…”

Antioxidant and anti‐inflammatory effects of the monocarbonyl curcumin analogs B2BRBC and C66 in monocrotaline‐induced right ventricular hypertrophy

“…At the first day of treatment, monocrotaline (Sigma, St Louis) was administered as a single subcutaneous dose of 60 mg/kg dissolved in 0.5M HCl and pH adjusted to 7.4 with 0.2M NaOH. The same volume of pH‐adjusted physiological saline was injected into the control group of the rats.…”