Abstract 3632: Selective Delivery of siRNA Nanoparticles Targeting MEK Attenuates Experimental Pulmonary Hypertension
Background: Proliferation of vascular smooth muscle cells (VSMC) is considered to be a major pathological cause of pulmonary arterial hypertension (PAH), and mitogen-activated protein kinase kinase (MEK) pathway have been postulated to be involved in the process of cell proliferation. We investigated whether delivery of nanoparticles wrapping siRNA targeting MEK1/2 (siMEK/WL) into the lung attenuates monocrotaline (MCT)-induced pulmonary hypertension in rats.
Methods and Results: We developed an intravenous delivery system of siMEK using a novel nanoparticle technology. The nanoparticle was composed of siRNA and cationic liposome complexes wrapped with neutral lipids. In vitro study demonstrated that siMEK significantly inhibited the expression of MEK1/2 mRNAs and proteins in cultured VSMC. siMEK inhibited proliferation and induced apoptosis of VSMC. A rat model of PAH was produced by injection of MCT. After MCT injection, rats were administered biweekly systemic intravenous injection of 0.2 mg/kg siMEK/WL. Hemodynamic measurements and histological analysis were performed on Day 21. Treatment with siMEK/WL significantly attenuated increases in right ventricular systolic pressure and right ventricular weight to body weight ratio in MCT rats. In addition, siMEK/WL were selectively accumulated in injured pulmonary arterial wall, and inhibited the expression of MEK1/2 mRNAs in the lung. Furthermore, siMEK/WL significantly inhibited hypertrophy of the pulmonary arterial wall in MCT rats.
Conclusions: siMEK/WL, a novel siRNA delivery system, selectively accumulated in injured pulmonary arterial wall and attenuated MCT-induced pulmonary hypertension. Thus, inhibition of MEK by siMEK/WL may be a new therapeutic strategy for the treatment of PAH.