Journal Article

ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension

Viswanathan, Gayathri, Novoyatleva, Tatyana, Schermuly, Ralph T., Boehm, Mario, Ghofrani, Hossein A., Tian, Xia, Weissmann, Norbert, Budas, Grant R., Seeger, Werner, Hinojosa-Kirschenbaum, Ford, Liles, John T., Kojonazarov, Baktybek, Veeroju, Swathi, Grimminger, Friedrich

2018

Overview

Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.

• Publisher: Oxford University Press
• Subject: Animals / Apoptosis / Biopsy, Needle / Cardiotonic Agents / Cells, Cultured / Disease Models, Animal / Fibroblasts / Fibroblasts - cytology / Fibroblasts - drug effects / Gene expression / Heart failure / Hemodynamics - physiology / Hypertension, Pulmonary - drug therapy / Hypertension, Pulmonary - pathology / Hypertrophy, Right Ventricular - prevention & control / Hypoxia / Immunohistochemistry / Kinases / Laboratory animals / MAP Kinase Kinase Kinase 5 - administration & dosage / MAP Kinase Kinase Kinase 5 - antagonists & inhibitors / Medical prognosis / Mice / Oxidative stress / Phosphorylation / Proteins / Pulmonary arteries / Pulmonary Artery - drug effects / Pulmonary hypertension / Random Allocation / Rats / Risk Assessment / Rodents / Smooth muscle / Veins & arteries