DOI: 10.1161/circ.148.suppl_1.12393 ISSN: 0009-7322

Abstract 12393: Pexidartinib Ameliorates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

Kazuto Nishiura, Tetsuro Yokokawa, Tomofumi Misaka, Shunsuke Miura, Yusuke Tomita, Akihiko Sato, Masayoshi Oikawa, Koichi Sugimoto, Kazuhiko Nakazato, Yasuchika Takeishi
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Background: Pulmonary arterial hypertension (PAH) is a life-threatening disease caused by pulmonary artery remodeling, inflammation, and altered immune responses. Lungs from PAH patients show that accumulation of perivascular macrophages is a key factor for the development of pulmonary artery remodeling, which leads to right ventricular failure. However, pharmacological inhibition of this pathway for treating PAH has not been thoroughly examined. Pexidartinib inhibits macrophage proliferation and polarization, thus can be a candidate for treating PAH.

Objective: To investigate the effect of pexidartinib in PAH.

Methods: Male Sprague-Dawley rats were divided into 4 groups: control, pexidartinib treated, monocrotaline (MCT)-exposed, pexidartinib treated and MCT-exposed rats. Right ventricular hemodynamic changes, right ventricular hypertrophy, and pulmonary artery morphological features were examined. Pulmonary artery perivascular macrophage infiltration was determined by immunofluorescence of CD68 and arginase-1 (M2 macrophage marker).

Results: Immunofluorescence of lungs from MCT-exposed PAH rats showed perivascular CD68- and arginase-1-positive macrophage infiltration (P < 0.05, each) and muscularization of pulmonary arteries (P < 0.05) compared to controls. Treatment of pexidartinib inhibited perivascular CD68- and arginase-1-positive macrophage infiltration (P < 0.05, each) and attenuated right ventricular systolic pressure and the right ventricle to the left ventricle plus septum ratio (RV/LV+IVS) in MCT-exposed PAH rats (Figure 1).

Conclusion: Pexidartinib treatment prevented MCT-induced PAH and right ventricular hypertrophy by inhibiting perivascular macrophage infiltration and M2 macrophage polarization in rat pulmonary arteries. Therefore, pexidartinib may be a promising drug for the treatment of PAH.

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