Rein-Smith, Chantelle M.a; Church, Frank C.a,b
Fibrinolysis is traditionally viewed as a response to coagulation, mediated by the interaction of activator and inhibitor proteins, leading to fibrin clot breakdown. The plasminogen activator system plays a central role in the initiation of fibrinolysis in that activation of members of this family, including tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), leads to proteolytic activation of plasminogen to plasmin and subsequent clot dissolution (Fig. 1). To ensure appropriate temporal and spatial control of clot lysis, the plasminogen activator system is regulated by several inhibitors including the serine protease inhibitors (serpins) plasminogen activator inhibitor (PAI)-1, PAI-2, and α2-antiplasmin (α2-AP). PAIs bind to and inactivate tPA and uPA, whereas α2-AP directly inhibits plasmin activity.
The regulation of fibrinolysis in the pathophysiology of thrombosis and hemorrhage has been extensively studied. In this review, we discuss the role of the plasminogen activator system and its inhibitors in the cause and treatment of cancer, inflammation, and cerebrovascular disease.
FIBRINOLYSIS AND CANCER
The plasminogen activator system is involved in tumor growth, invasion, and metastasis. In addition to fibrin clots, plasmin has several other targets for proteolysis, including extracellular matrix (ECM) proteins and matrix metalloproteases. Whereas degradation of the ECM serves a physiological role during tissue remodeling, wound healing, and embryogenesis, these processes also facilitate tumor cell invasion and metastasis.
Plasminogen receptors and cancer
Plasminogen receptors serve to localize the activation of plasminogen to plasmin by forming a complex of plasminogen receptor, plasminogen, and tPA. One plasminogen receptor, Annexin A2, is expressed on the surface of epithelial cells, vascular endothelial cells, and macrophages. Its expression is elevated in several cancers and is associated with increased tumor growth rates, metastasis, and chemoresistance .
The uPA receptor (uPAR) is also vital for cellular migration as it localizes uPA to the cell surface and directs degradation of the ECM. uPAR also associates indirectly with the low-density lipoprotein receptor-1 (LRP-1) via interaction with the uPA–PAI-1 complex, leading to intracellular signaling. Rao et al.[2▪] demonstrated that implantation of uPAR overexpressing cells led to increased brain tumor invasion and vascularity, suggesting that soluble uPAR derived from tumors is able to directly influence the migration of human umbilical vein endothelial cells (HUVECs) and tumor angiogenesis. At the cell surface, uPAR has also been shown to associate with the formyl peptide receptor-1 and β1 integrins to induce downstream intracellular signaling .
Recently, other ligands of plasminogen receptors have been identified, including angiogenin, a pro-angiogenic protein. Angiogenin was elevated in highly aggressive breast cancer cells, and co-localized with Annexin A2 and uPAR on the cell surface. The interaction of uPA and uPAR was enhanced in the presence of angiogenin, suggesting that angiogenin aids in the formation of plasmin and enhances breast cancer cell migration, invasion, and metastasis .
Plasminogen activator inhibitors and cancer
The endogenous inhibitor of uPA, PAI-1, not only inhibits the breakdown of fibrin clots via inhibition of uPA-mediated plasmin generation, but also influences cellular processes involved in cancer progression. Increased expression of PAI-1 has been associated with poor clinical prognosis in several cancer types. In urothelial and cervical cancer cells, knockdown or inhibition of PAI-1 was associated with a significant inhibition of the cell cycle at G1. This cell cycle arrest was also associated with an increase in cell cycle inhibitors and a decrease in cyclin and cyclin-dependent kinase complexes. Furthermore, xenograft tumor growth of cells with stable PAI-1 knockdown demonstrated a smaller tumor volume, reduced proliferation, and reduced cyclin D3 levels [5▪▪]. Ibrahim et al. also demonstrated that PAI-1 expression negatively regulates tPA-dependent hematopoietic regeneration in the bone marrow following myeloablation, suggesting that elevated PAI-1 expression not only enhances tumorigenesis, but also inhibits the recovery process following myeloablative treatment.
PAI-2 expression has been associated positively and negatively with cancer, depending on the cancer type. The role of PAI-2 in hepatocellular carcinoma (HCC) was examined by Zhou et al., who showed that positive PAI-2 staining correlates with decreased tumor size and increased survival in patients with HCC, whereas negative PAI-2 staining correlates with portal vein tumor thrombosis. PAI-2 is also upregulated in brain metastatic cells, and its expression level in primary lung adenocarcinomas was associated with metastatic disease in the brain [8▪▪]. A similar result was obtained for neuroserpin, a predominantly neuronally expressed inhibitor of tPA. Neuroserpin was upregulated in the brain metastases from primary breast tumors, but not in metastases to the bone or lungs. Neuroserpin knockdown inhibited primary tumor cell metastasis, suggesting that inhibition of tPA by neuroserpin is protective against brain metastasis from primary breast tumors [8▪▪]. As both PAI-2 and neuroserpin are overexpressed in brain metastases, this suggests that inhibition of the plasminogen activator system may give an advantage in the formation of brain metastases.
Protease nexin-1 (PN1) is a plasminogen activator system inhibitor that is highly expressed in the brain and prostate. In addition to its role in clot maintenance, PN1 has a role in neuronal proliferation, neurite outgrowth, and tumor growth and metastasis. An inverse association between PN1 levels and Hedgehog signaling in the brain suggests that PN1 may regulate Hedgehog signaling in cancer. Recent work by McKee et al. has shown that PN1 expression inhibits Hedgehog signaling in prostate adenocarcinoma cells by reducing sonic Hedgehog expression. This inhibition led to inhibition of tumor growth and angiogenesis in the models of prostate cancer, and absence of PN1 led to increased susceptibility to prostate tumors.
Inhibition of the plasminogen activator system as cancer therapy
Taken together, the above evidence suggests that plasminogen activator system components and their inhibitors may be viable drug target candidates as the majority of these components are circulating or are cell surface expressed.
Pyrazole-based compounds that bind to and inhibit uPAR inhibit the proliferation, invasion, and migration of MDA-MB-231 breast cancer cells via an increase in apoptosis . Similarly, peptides that interfere with the minimal sequence of uPAR required to induce cell motility and angiogenic responses also demonstrated efficacy in vitro in HUVEC and fibrosarcoma cell lines .
Numerous miRNAs have been discovered that regulate the key processes involved in tumorigenesis, cancer progression, and metastasis. Salvi et al. identified miR193a as a negative regulator of uPA expression in two HCC cell lines and in tissue samples from HCCs. Overexpression of miR193a led to decreased proliferation and increased apoptosis. Interestingly, inhibition of PAI-1 expression in endometrial cells by miRNA145 also inhibited the cellular proliferation and invasiveness of endometriotic cells , suggesting that miRNAs are useful tools in targeting the plasminogen activator system and its inhibitors in cancers in which the plasminogen activator axis has been thrown off balance.
FIBRINOLYSIS AND INFLAMMATION
The fibrinolytic system is among the many systems activated in the presence of inflammation. Many different cell types are known to produce members of the plasminogen activator family, as well as plasminogen activator system inhibitors, during inflammation.
Fibrinolysis in sepsis and infection
During severe infection or sepsis, the body activates a wide range of defense mechanisms culminating in a systemic inflammatory state. Johansson et al. have shown that in patients with sepsis, tPA correlated with biomarkers of endothelial activation, including PAI-1, and the PAI-1 level was a predictor of 28-day mortality. Kager et al.[15▪] examined the role of α2-AP in melioidosis, a septic disease caused by the bacterium Burkholderia pseudomallei. Patients with melioidosis had increased plasma α2-AP levels and the absence of α2-AP in a mouse model of melioidosis demonstrated enhanced bacterial growth, increased infection in distant organs, increased inflammatory cytokine production, and overall increased systemic inflammation. These results suggest that inhibition of plasmin by α2-AP is protective during melioidosis, but PAI-1-mediated inhibition of plasmin generation is detrimental in sepsis.
Sepsis is also associated with the early activation of coagulation and fibrinolysis following damage to the endothelium. In a human endotoxemia study, administration of lipopolysaccharide led to a systemic inflammatory response, including increased fibrinolysis, during the early stages of disease . Upon stimulation of Toll-like receptor (TLR)-4 in macrophages, intracellular signaling events led to the binding of several transcription factors to the PAI-2 promoter to promote expression of PAI-2 mRNA . Depletion of PAI-2 in macrophages induced IL-1β production upon stimulation of TLR-4 and TLR-2 or in the presence of Escherichia coli infection . In endothelial cells, treatment with lipopolysaccharide led to packaging of PAI-2 into vesicles within the trans-Golgi network that are shuttled to the plasma membrane, increasing the secretion of PAI-2 from the cell . Together, these results suggest that increased expression of PAI-2 through TLR-mediated mechanisms leads to decreased production of inflammatory mediators and that PAI-2 may play a protective role in infection and sepsis by limiting inflammatory tissue damage.
In addition to endotoxemia, other infectious agents alter the function of the plasminogen activator system. Several strains of Streptococcus pyogenes secrete the cluster 2b streptokinase (SK2b), an activator of plasminogen that functions optimally when plasminogen is bound to the bacterial cell. Recent work has demonstrated that the central β domain of SK2b is necessary to bind plasminogen to the bacterial surface, conferring optimal function and virulence . Infection with the enteric nematode Heligmosomoides bakeri involves a Th2 T-cell cytokine response and recruitment of multiple inflammatory cell types, including activated monocytes and macrophages that are stores for PAI-2. Infection of mice with H. bakeri increased the intestinal PAI-2 levels, and mice unable to express PAI-2 demonstrated decreased worm clearance, impaired infiltration of macrophages, and inhibition of Th2 cytokine release [21▪]. These results suggest that activators and inhibitors of the plasminogen activator system regulate the virulence of infectious organisms and the immune response of the body to these infections.
Activated protein C (aPC) is used in the treatment of severe sepsis as it has anti-inflammatory and profibrinolytic properties. Recent work by Boulaftali et al.[22▪▪] demonstrated that endothelial cell PN1 abrogates the cytoprotective effect of aPC when it is bound to EPCR. Blocking or reducing PN1 decreased the vascular barrier protection and antiapoptotic functions of aPC in endothelial cells. Additionally, vascular endothelial growth factor-induced hyperpermeability of the skin was reduced by injection of aPC in wildtype mice but not in PN1 knockout mice.
Fibrinolysis and trauma
Traumatic injury is often associated with disseminated intravascular coagulopathy characterized by a systemic inflammatory response involving the release of procoagulants, such as tissue factor. Infusion of tissue factor in rats led to the development of disseminated intravascular coagulopathy, consumption of α2-AP, and enhanced plasmin-mediated fibrinolysis . A recent study demonstrated that only 5% of trauma patients had severe fibrinolysis, but 57% had evidence of moderate fibrinolysis. Patients with fibrinolytic activation also had an increased 28-day mortality rate compared with those without fibrinolytic activation, suggesting that the magnitude of fibrinolytic activation correlated with poor clinical outcomes . These results suggest that fibrinolytic activation is present in the majority of trauma patients, due in part to the consumption of α2-AP and, therefore, increased plasmin levels.
Fibrinolysis and inflammatory joint disease
Patients with psoriatic arthritis and rheumatoid arthritis have intense local inflammatory responses driven by inflammatory cytokines such as tumor necrosis factor (TNF)-α. Raghu et al. demonstrated that elimination of plasminogen in a mouse model predisposed to polyarthropathy by TNF-α overexpression worsened the incidence and severity of arthritis in the paw joints. A comparison of psoriatic arthritis patients treated with TNF-α inhibitors or traditional antirheumatic drugs demonstrated that treatment with TNF-α led to significantly lower levels of tPA and PAI-1 than treatment with traditional therapies [26▪]. Systemic sclerosis is characterized by endothelial cell injury, extravasation of white blood cells, and collagen accumulation in the dermal layer of the skin. uPAR is inhibited in the endothelial cells from systemic sclerosis patients, preventing angiogenesis . Recent work has shown that miRNA193b, which inhibits uPA production, is significantly downregulated in the fibroblasts of systemic sclerosis patients, leading to an increase in uPA expression and increased proliferation of vascular smooth muscle cells, contributing to the vasculopathy common in systemic sclerosis .
Fibrinolysis and airway disease
Increased levels of uPA, uPAR, and PAI-1 have been found in the sputum of patients with asthma, chronic obstructive pulmonary disease, and cystic fibrosis, whereas PAI-2 is also elevated in the epithelium of patients with asthma and chronic obstructive pulmonary disease. However, overexpression of uPA, uPAR, PAI-1, or PAI-2 did not alter proliferation or apoptosis in bronchial epithelial cells [29▪]. In airway smooth muscle cells, incubation of cells with plasminogen or plasmin increased the release of interleukin (IL)-6 and IL-8, and this effect was attenuated by the addition of α2-AP [29▪]. In a mouse model of allergen-induced airway inflammation, mice lacking Annexin A2 had decreased infiltration of inflammatory cells and IL-6 levels in the bronchoalveolar lavage fluid, suggesting that Annexin A2 regulates the plasminogen-induced cytokine release . Overall, these results suggest that members of the plasminogen activator system and its inhibitors play cell-type-specific roles in modulating the function of airway cells and may play a role in the pathogenesis of airway disease.
Fibrinolysis and atherosclerosis
Several monocyte subtypes are involved in atherothrombosis. Recently, the expression of vascular endothelial growth factor receptor-1 was positively correlated with PAI-1 antigen levels in CD14 and CD16-positive monocytes, whereas IL-6R expression was decreased in this monocyte population [31▪]. Additional studies on the role of the plasminogen activator system in CAD in patients with increased inflammation showed that polymorphisms within the gene encoding PAI-2 significantly increased the risk of CVD and interacted with polymorphisms within the LRP-1 gene .
Targeting PAI-1 or PAI-2 is an attractive therapeutic goal, as the levels of both proteins have been associated with CAD. A recent study discovered that miRNA-421 and miRNA-30c directly interact with the promoter of the SERPINE1 gene, which encodes PAI-1, and inhibited PAI-1 expression in HUVECs. Interestingly, miRNA-421 levels correlated positively with PAI-1 activity in the plasma of 40 patients with venous thrombosis . Although paradoxical, these results suggest that expression of PAI-1 is under the control of miRNA-421 and may be a useful biomarker of inflammatory and thrombotic disorders. Recent studies also suggest that PAI-1 is under the control of the human circadian system, potentially explaining the peak of cardiovascular events in the morning hours [34▪].
Fibrinolysis and metabolic disease
Diabetes and hyperglycemia are also characterized by systemic activation of inflammation along with atherothrombosis, vascular inflammation, and impaired fibrinolytic activity. Recent work by Dai et al. has shown that hyperglycemia leads to a decrease in cell-surface fibrinolytic activity on brain endothelial cells because of a decrease in the expression of Annexin A2. Advanced end-product glycation of Annexin A2 also occurred, which inhibited the binding of tPA and plasminogen to the surface of the cells, subsequently inhibiting plasmin generation. These results suggest that diabetes and hyperglycemia can directly affect fibrinolysis by modifying proteins of the plasminogen activator and plasminogen activator inhibitor systems.
FIBRINOLYSIS AND CEREBROVASCULAR DISEASE
tPA is present in the intravascular space, where it performs a predominantly thrombolytic function, and in the central nervous system, where its role involves the regulation of axonal growth, long-term potentiation, motor learning, and controlling blood–brain barrier (BBB) permeability. tPA is widely administered following stroke in order to quickly lyse cerebral thrombi and to re-canalize the occluded vessel. Despite the benefits of tPA following stroke, tPA can also play a deleterious role in stroke by increasing vascular permeability, inducing proinflammatory cytokine production, and increasing neuronal death in nearby cells.
Fibrinolysis and ischemic stroke
Increased tPA levels promote neurovascular disruption following ischemic stroke and potentiate neurovascular damage in a mouse model of neurotrauma . Unexpectedly, administration of PAI-1 following neurotrauma increased cerebrovascular permeability. The complex of PAI-1 and tPA bound to LRP-1 lead to induction of matrix metalloprotease-3 and vascular permeability in wildtype mice, but not in mice lacking tPA, following brain injury. Additionally, Gelderblom et al.[37▪] demonstrated that in mice deficient in neuroserpin, infarct size and neurological outcomes were worse following cerebral ischemic stroke even though fibrinolytic activity in the brain was increased. Deficiency of neuroserpin also led to increased proinflammatory microglial activation, which was mediated by increased levels of tPA and signaling through tPA bound to LRP-1. Signaling via LRPs is highly ligand dependent, as both enzymatically active and inactive tPA activate signaling in PC12 and N2a neuronal-like cells [38▪]. These results suggest that signaling of tPA through LRP-1 is correlated with increased damage following ischemic stroke.
However, others have demonstrated that the release of tPA from cortical neurons is protective in the setting of cerebral ischemia. Increased levels of tPA released at the synaptic terminal in response to low glucose levels protect neurons against excitotoxic cell death . An et al.[40▪] report that overexpression of neuronal tPA, or treatment with recombinant tPA, also protects neurons from the deleterious effects of metabolic disease independently of tPA cleavage of plasminogen. Exposure to oxygen and glucose deprivation induced tPA release from murine neurons and downstream signaling, leading to glucose uptake in astrocytes and cerebral endothelial cells. Additionally, tPA induced the synthesis and release of lactic acid from astrocytes, which was taken up by neurons, protecting these neurons from death induced by oxygen and glucose deprivation.
In cerebral ischemia initiated by oxygen and glucose deprivation, mice lacking PN1 had increased neuronal death following ischemia. PN1 expression was induced after oxygen and glucose deprivation in the brain, suggesting that PN1 is an endogenous neuroprotectant in cerebral ischemia . Taken together, these results highlight the various roles of tPA in exacerbation of and protection from ischemic stroke.
Recent work by Wang et al. has demonstrated that treatment with low-dose tPA and Annexin A2 significantly decreased cerebral infarction and improved neurological function after a stroke when compared with treatment with high-dose tPA alone. The mechanism behind the improvement seen with combination therapy may be that less tPA is present at BBB than with high-dose tPA alone, leading to less BBB disruption, less tPA penetration into the nearby neurons, and improved long-term outcomes.
Fibrinolysis and amyloid deposition diseases
Neuroserpin is elevated in the brains of Alzheimer's disease patients, leading to decreased plasmin generation and decreased proteolytic clearance of β-amyloid plaques. Increased neuroserpin may be a result of the activation of the thyroid hormone system . Recent evidence also suggests that fibrinogen is deposited in the neurovasculature of patients with Alzheimer's disease, where it interacts with β-amyloid and leads to increased formation of blood clots and increased severity of cerebral amyloid angiopathy [44▪]. Taken together, these results suggest that tPA plays a protective role in the pathogenesis of Alzheimer's disease by increasing plasmin generation, which can enhance the clearance of amyloid-β plaques and can also indirectly aid in the cleavage of fibrin clots within the vasculature of Alzheimer's disease patients.
Overall, the plasminogen activator system is a complex system of activators, receptors, and inhibitors of clot breakdown, whose roles are not limited to the cardiovascular system, but include functions in the formation and progression of cancer, pathogen virulence, airway disease, metabolic disease, chronic inflammatory diseases, diseases of protein aggregation, maintenance of neuronal plasticity, and cellular proliferation and death. These attributes make the plasminogen activator system one of the most complex and most widely studied systems in physiology. The recent work outlined in this review has shed light on the advances in a wide variety of fields and organ systems affected by plasminogen activator system function and inhibition.
F.C.C. is supported in part by an American Heart Association grant.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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This study showed that fibrinogen is deposited in the brains of Alzheimer's disease patients, and this deposition correlated with the level of cerebral amyloid angiopathy severity.