The anti-fibrinolytic SERPIN, plasminogen activator inhibitor 1 (PAI-1), is targeted to and released from catecholamine storage vesicles

Abstract

Recent studies suggest a crucial role for plasminogen activator inhibitor-1 (PAI-1) in mediating stress-induced hypercoagulability and thrombosis. However, the mechanisms by which PAI-1 is released by stress are not well-delineated. Here, we examined catecholaminergic neurosecretory cells for expression, trafficking, and release of PAI-1. PAI-1 was prominently expressed in PC12 pheochromocytoma cells and bovine adrenomedullary IntroductionPlasminogen activator inhibitor type 1 (PAI-1) is a member of the serine protease inhibitor (SERPIN) superfamily. Its major recognized function is regulation of the fibrinolytic system by rapidly inhibiting the plasminogen activators tissue plasminogen activator (tPA) and urokinase (uPA), thus preventing activation of plasminogen to plasmin. 1 Elevated plasma concentrations of PAI-1 have been observed in a variety of thrombotic disorders, including deep vein thrombosis, 2 myocardial infarction, [3][4][5] and disseminated intravascular coagulation. 6 Recent studies have suggested an important association and role for the stress response in promoting thrombotic events. Mental and physical stress substantially decrease fibrinolytic activity. 7 Acute stress and chronic stress are associated with elevated plasma concentrations of PAI-1 antigen in humans and in rodent models. 8,9 Chronic stress is associated with elevated plasma PAI-1 antigen concentrations in middle-aged men. 8 Studies using a restraint stress paradigm in mice demonstrated a striking increase in plasma PAI-1 antigen concentrations in response to acute stress. 9 In addition, the PAI-1 response correlated with tissue thrombosis, particularly in older stressed mice. 9 Moreover, much less tissue thrombosis was induced by restraint stress in both young and aged PAI-1 deficient mice compared with age-matched wildtype mice. 9 These results demonstrate that increased expression and release of PAI-1 in response to physiologic and pathologic stress increase the prothrombotic potential, thus promoting thrombotic complications under stressful conditions. Hence, these results suggest a crucial role for PAI-1 in mediating stress-induced hypercoagulability and thrombosis. However, the mechanisms by which PAI-1 plasma concentrations are increased by stress are not well delineated. Of note, the stress response is characterized by, and in large part mediated by, activation of the sympathoadrenal system causing exocytotic release of amines and proteins from catecholamine storages vesicles of the adrenal medulla and sympathetic neurons. 10 Interestingly, in the above mentioned murine studies, restraint stress was associated with a pronounced increase in PAI-1 mRNA expression in the adrenal medulla. 9 However, the intracellular trafficking of PAI-1 and its release from these cells (ie, via regulated versus constitutive secretory pathways 11,12 ) are fundamental issues that have not been elucidated. Therefore, we tested the hypothesis that PAI-1 is targeted to and released directly by exocytosis from adrenomedullary catecholamine storag...

ST-Segment Elevation Myocardial Infarction Related to Potential Spontaneous Coronary Thrombosis in Pheochromocytoma Crisis

“…First, excessively secreted catecholamines may increase the levels of factor VIII and VWF antigen and activate platelets, resulting in hypercoagulability (5). Second, the inflammatory cytokines and procoagulants secreted by tumor cells, such as the plasminogen activator inhibitor-1 which is stored in catecholamine storage vesicles and co-released with catecholamines, may play a crucial role in inducing hypercoagulability (9,10). Third, the coronary slow flow, possibly caused by microvascular dysfunction following vasospasm due to aberrant catecholamines secretion (11,12), may also participate in this pathologic process.…”

Peptidergic regulation of plasminogen activator inhibitor‐1 gene expression in vivo

“…Thus, the increase in plasma PAI‐1 in response to PACAP may be the result of both the induction of PAI‐1 biosynthesis and PACAP‐mediated secretion of PAI‐1 from adrenomedullary chromaffin cells and possibly other sites. Indeed, we have recently demonstrated that PAI‐1 is targeted at the regulated pathway of secretion (to catecholaminergic storage vesicles) in chromaffin cells and is released from these cells in response to chromaffin cell secretagogues and sympathoadrenal activation .…”

“…We and others have demonstrated that components of the plasminogen activation pathway are expressed in the chromaffin cells of the adrenal medulla and in sympathetic neurons [10,[16][17][18][19][20][21][22][23][24][25][26]. These sites may provide an important source of fibrinolytic pathway molecules in the circulation in response to stress, and, in addition, local modulation of the plasminogen activation pathway plays a major role in the regulation of catecholamine secretion [20][21][22][26][27][28]. Recent studies have shown that stress-mediated induction of PAI-1 expression is tissue and cell specific and is especially prominent in adrenomedullary chromaffin cells [10].…”

Effects of environmental and social stressors on biological rhythms

“…Induction of restraint in rats induced an increase in plasma corticosterone with HPA axis activation 58,59) , as well as upregulation of pineal or plasma melatonin 58,60) . In mice, restraint can induce catecholamine release and a parallel increase in PAI-1 production and gene expression 61,62) .…”