Interventions Against the Molecular Etiology of BMPR2-induced PAH

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DESCRIPTION (provided by applicant): Idiopathic pulmonary arterial hypertension (PAH) is a lethal disorder characterized by pulmonary arterial remodeling, increased RVSP, chronic inflammation and vasoconstriction. The familial form of PAH is usually due to mutations in the type 2 receptor for Bone Morphogenic Protein, BMPR2. Examination of the consequences of BMPR2 mutation in transgenic mice and in cell culture, corroborated by human data from the literature, implicates several pathways that converge to promote PAH. Our preliminary data indicate that BMPR2 mutation causes dephosphorylation of cofilin, likely through direct regulation of LIMK. Dephosphorylation of cofilin drives the glucocorticoid receptor (GR) into the nucleus, where in the absence of ligand it causes both abnormal signaling and glucocorticoid insensitivity. This paradoxically causes some GR-dependent agonist effects, thus weight gain and high blood glucose in BMPR2 mutant humans and mice, but causes inability to signal through others, leaving BMPR2 mutation carriers susceptible to the chronic inflammation, which glucocorticoids are meant to suppress. Glucocorticoid activation and elevated blood glucose can lead to elevated reactive oxygen species (ROS) through mitochondrial ROS production. Our data indicate that BMPR2 mutant mice have a ~2x increase in lipid peroxidation in whole lung, increased pulmonary vascular peroxidized lipid staining, and increased expression of ROS-responsive genes. Also, all BMPR2 mutations tested in cultured smooth muscle cells lead to a ~2x increase in peroxide formation, and RNA expression changes suggestive of increased ROS and a shift to aerobic glycolysis and glutaminolysis. Aberrant glucocorticoid receptor signaling leads to increased vascular adhesion and permeability by monocytes, and this in combination with increased ROS may drive recruitment of monocytes and alternative (M2) macrophage activation, which can drive pathologic changes to the pulmonary vasculature in their microenvironment. To synthesize these data, we hypothesize that the important early etiologic changes caused by BMPR2 mutation are aberrant glucocorticoid receptor signaling and increased ROS, which drive increased recruitment of monocytes, alternative (M2) macrophage activation, and remodeling of the pulmonary vasculature. This chronic inflammatory state in precapillary pulmonary arteries leads to PAH through loss of normal vasoreactivity, increased formation of thrombi, and a predisposition to proliferation caused by microenvironmental changes brought about by interactive signaling between BMPR2 mutant vascular cells and macrophages. This study will clarify the early molecular etiology of BMPR2-induced PAH, as well as providing information about BMP regulation of inflammation with implications to a host of diseases.