Pulmonary hypertension (PH) is a progressive disease with high morbidity and mortality with mutations in BMPR2 a predisposing factor in this disease. A hallmark of the subcellular alterations in this disease, in man and in experimental models, includes enlarged vacuolated endothelial and smooth muscle cells with increased endoplasmic reticulum and Golgi stacks ("megalocytosis") in pulmonary arterial lesions. We propose a novel disease-initiating mechanism at the subcellular level - a dysfunction of intracellular trafficking (the Golgi blockade hypothesis). We shall investigate this mechanism in human PH and in experimental models (monocrotaline, hypoxia, BMPR2R899X mutation) using in vivo-derived materials and in experiments in cell culture. Predicted consequences include trapping of vesicle tethers, SNAREs and SNAPs in the Golgi and subcellular mislocalization of N-ethylmaleimide sensitive factor (NSF), and of cargo such as eNOS and vasorelevant growth factor recetors (SNAREing pulmonary hypertension), Distal consequences include enhanced cytokine and growth factor signaling, promitogenic signaling and DNA synthesis, resistance to apoptosis, increased cell size and cell migration and thus reduction of the vascular lumen.
In Aim 1 (in vivo studies) we shall link the Golgi blockade hypothesis to the pathophysiology of idiopathic PH in man, in the monocrotaline and hypoxia models of PH in the rat, and in the BMPR2 R899X transgenic mouse.
In Aim 2 (cell culture studies) we shall investigate the initiation mechanisms that lead to Golgi blockade and defects in intracellular trafficking in response to MCTP, hypoxia and BMPR2 mutants with a focus on NSF and the proximal mechanistic events involved.
In Aim 3 (cell culture studies) we shall investigate some of the distal trafficking consequences of disruption of intracellular trafficking by MCTP, hypoxia and BMPR mutants.
. Pulmonary arterial hypertension (PH) is a progressive fatal lung disease in man. We propose an all together novel way of thinking about the cause of this fatal disease. We suggest that the endothelial and smooth muscle cells that line the arterial blood vessels in the lung become bigger and increase in number because of a defect in cellular machinery that handles the movement of proteins within these cells. This leads to a blockage of the blood vessels. The proposed mechanism opens up new ways of thinking about how to treat this disease.
|Lee, Jason E; Yang, Yang-Ming; Yuan, Huijuan et al. (2013) Definitive evidence using enucleated cytoplasts for a nongenomic basis for the cystic change in endoplasmic reticulum structure caused by STAT5a/b siRNAs. Am J Physiol Cell Physiol 304:C312-23|
|Khan, Rasel; Lee, Jason E; Yang, Yang-Ming et al. (2013) Live-cell imaging of the association of STAT6-GFP with mitochondria. PLoS One 8:e55426|
|Lee, Jason E; Yuan, Huijuan; Liang, Feng-Xia et al. (2013) Nitric oxide scavenging causes remodeling of the endoplasmic reticulum, Golgi apparatus and mitochondria in pulmonary arterial endothelial cells. Nitric Oxide 33:64-73|
|Lee, Jason E; Yang, Yang-Ming; Liang, Feng-Xia et al. (2012) Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function. Am J Physiol Cell Physiol 302:C804-20|
|Lee, Jason E; Patel, Kirit; Almodovar, Sharilyn et al. (2011) Dependence of Golgi apparatus integrity on nitric oxide in vascular cells: implications in pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 300:H1141-58|
|Sehgal, Pravin B; Lee, Jason E (2011) Protein trafficking dysfunctions: Role in the pathogenesis of pulmonary arterial hypertension. Pulm Circ 1:17-32|
|Sehgal, P B (2010) Interleukin-6 induces increased motility, cell-cell and cell-substrate dyshesion and epithelial-to-mesenchymal transformation in breast cancer cells. Oncogene :|
|Sehgal, Pravin B; Mukhopadhyay, Somshuvra; Patel, Kirit et al. (2009) Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques. Am J Physiol Lung Cell Mol Physiol 297:L729-37|
|Lee, Jason; Reich, Reuben; Xu, Fang et al. (2009) Golgi, trafficking, and mitosis dysfunctions in pulmonary arterial endothelial cells exposed to monocrotaline pyrrole and NO scavenging. Am J Physiol Lung Cell Mol Physiol 297:L715-28|
|Mukhopadhyay, Somshuvra; Lee, Jason; Sehgal, Pravin B (2008) Depletion of the ATPase NSF from Golgi membranes with hypo-S-nitrosylation of vasorelevant proteins in endothelial cells exposed to monocrotaline pyrrole. Am J Physiol Heart Circ Physiol 295:H1943-55|