Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs?

Abstract

Histological and electron microscopic studies over the past four decades have highlighted “plump,” “enlarged” endothelial, smooth muscle, and fibroblastic cellular elements with increased endoplasmic reticulum, Golgi stacks, and vacuolation in pulmonary arterial lesions in human and in experimental (hypoxia and monocrotaline) pulmonary arterial hypertension. However, the contribution of disrupted intracellular membrane trafficking in the pathobiology of this disease has received insufficient attention. Recent studies suggest a pathogenetic role of the disruption of intracellular trafficking of vasorelevant proteins and cell-surface receptors in the development of this disease. The purpose of this essay is to highlight the molecular regulation of vesicular trafficking by membrane tethers, SNAREs and SNAPs, and to suggest how their dysfunction, directly and/or indirectly, might contribute to development of pulmonary arterial hypertension in experimental models and in humans, including that due to mutations in bone morphogenetic receptor type 2.

Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension

“…Mechanistically, this loss of cav-1 from caveolae/rafts results from the trapping of cav-1 in the Golgi organelle (reviewed in Refs. 42,43) from where this trapped cav-1 can aberrantly traffic to other cytoplasmic compartments. Finally, that scaffolding domain mutants of cav-1 were equally effective in inhibiting transcriptional IL-6/STAT3 signaling compared with WT cav-1 (Fig.…”

“…caveolin-1; signaling endosome; monocrotaline PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by the reduction of the lumen of medium-sized pulmonary arteries by proliferating, enlarged, vacuolated, and apoptosis-resistant ("megalocytotic") pulmonary arterial endothelial (PAEC) and smooth muscle (PASMC) cells (42,43). We (24, 26 -28, 41-43, 47) recently proposed that dysfunction of vesicle tethers, soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs), and SNAP receptors (SNAREs), leading to disruptions of intracellular trafficking from the Golgi to plasma membrane (centrifugal) and the plasma membrane to cell interior (centripetal) directions might represent a key subcellular mechanism leading to the changes observed in endothelial and vascular smooth muscle cells in PAH.…”

“…However, considerations of centripetal signaling from the plasma membrane to the cell interior in the pulmonary hypertension literature have largely represented transcytoplasmic transit of activated signaling molecules as taking place exclusively as a soluble cytoplasmic process (reviewed in Refs. 42,43).…”

Golgi, trafficking, and mitosis dysfunctions in pulmonary arterial endothelial cells exposed to monocrotaline pyrrole and NO scavenging

“…Neointima development, thrombotic obliteration of arterial lumen, and development of plexiform lesions, reminiscent of human PAH, have also been reported with MCT when combined with partial pneumonectomy (44, 65 and citations therein). Additionally, perivascular/adventitial infiltrative cells and their cytokine contributions (such as IL-6) and transcription factors activated by such cytokines (STAT3 and NF-B) have been posited as contributory factors in the development of disease in this model (2,14,15,30,41,64).Over the last two decades bovine PAECs and PASMCs in culture exposed to MCTP have been used as experimental models to investigate some of the cellular, subcellular, and biochemical changes elicited by MCTP (18,25,26,30,[38][39][40][41][42]48,49,[53][54][55]57,61,66). A single exposure of confluent bovine PAEC cultures to MCTP for as short a time as 2 min leads to apoptosis of a small subset of cells with the development of marked megalocytosis of cells in the surviving, but still confluent, cell sheet 18 -24 h later (18,38,48,49,68, 73).…”

“…As with the in vivo observations (27, 34 -36), the cell culture studies showed dramatic increases in cell size, in Golgi stacks, and in the endoplasmic reticulum; increased DNA synthesis; and a unique premitotic cell cycle arrest despite the continued DNA synthesis resulting in hyperploidy of the affected cells (18,25,33,36,(39)(40)(41)48,49,55,57,61,66; reviewed in Refs. 53,54). Indeed, Roth and colleagues (18,48,49) posited as early as 1991 that these changes, observed in bovine PAEC culture, likely underlie the vascular remodeling seen in PAH in experimental animals.…”