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Frontiers in Physiology 2023Human plasma kallikrein (PKa) is obtained by activating its precursor, prekallikrein (PK), historically named the Fletcher factor. Human PKa and tissue kallikreins are... (Review)
Review
Human plasma kallikrein (PKa) is obtained by activating its precursor, prekallikrein (PK), historically named the Fletcher factor. Human PKa and tissue kallikreins are serine proteases from the same family, having high- and low-molecular weight kininogens (HKs and LKs) as substrates, releasing bradykinin (Bk) and Lys-bradykinin (Lys-Bk), respectively. This review presents a brief history of human PKa with details and recent observations of its evolution among the vertebrate coagulation proteins, including the relations with Factor XI. We explored the role of Factor XII in activating the plasma kallikrein-kinin system (KKS), the mechanism of activity and control in the KKS, and the function of HK on contact activation proteins on cell membranes. The role of human PKa in cell biology regarding the contact system and KSS, particularly the endothelial cells, and neutrophils, in inflammatory processes and infectious diseases, was also approached. We examined the natural plasma protein inhibitors, including a detailed survey of human PKa inhibitors' development and their potential market.
PubMed: 37711466
DOI: 10.3389/fphys.2023.1188816 -
Expert Opinion on Investigational Drugs Mar 2020: Plasma kallikrein is a mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in... (Review)
Review
: Plasma kallikrein is a mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in preclinical models. Human vitreous shows elevated plasma kallikrein levels in patients with DME. Because of the incomplete response of some patients to anti-VEGF agents, and the treatment burden associated with frequent dosing, there is still considerable need for VEGF-independent targeted pathways.: This review covers the role of plasma kallikrein in the pathogenesis of DME and the therapeutic potential of plasma kallikrein inhibitors. It discusses early clinical studies of plasma kallikrein pathway modulation for DME, which have been associated with some improvement in visual acuity but with limited improvement in macular edema. This review also highlights KVD001, which is furthest along the development pathway, THR-149, which has recently completed a phase 1 study, and oral agents under development.: Plasma kallikrein inhibitors have a potential role in the treatment of DME, with mixed functional/anatomic results in early clinical trials. Given the large unmet need in DME treatment, further studies are warranted.
Topics: Animals; Diabetic Retinopathy; Drug Development; Drugs, Investigational; Humans; Macular Edema; Plasma Kallikrein
PubMed: 31985300
DOI: 10.1080/13543784.2020.1723078 -
Cardiology in Review 2016Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein, and circulates in plasma bound to high molecular weight... (Review)
Review
Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein, and circulates in plasma bound to high molecular weight kininogen. Plasma prekallikrein is activated to plasma kallikrein by activated factor XII or prolylcarboxypeptidase. Plasma kallikrein regulates the activity of multiple proteolytic cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system, and the complement pathways. As such, plasma kallikrein plays a central role in the pathogenesis of thrombosis, inflammation, and blood pressure regulation. Under physiological conditions, plasma kallikrein serves as a cardioprotective enzyme. However, its increased plasma concentration or hyperactivity perpetuates cardiovascular disease (CVD). In this article, we review the biochemistry and cell biology of plasma kallikrein and summarize data from preclinical and clinical studies that have established important functions of this serine protease in CVD states. Finally, we propose plasma kallikrein inhibitors as a novel class of drugs with potential therapeutic applications in the treatment of CVDs.
Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Molecular Targeted Therapy; Plasma Kallikrein
PubMed: 25853524
DOI: 10.1097/CRD.0000000000000069 -
Blood Feb 2020
Topics: Kallikreins; Plasma Kallikrein; Prekallikrein; Proteolysis
PubMed: 32078685
DOI: 10.1182/blood.2019004339 -
Thrombosis and Haemostasis Sep 2013Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein (PK) and circulates in plasma bound to high molecular weight... (Review)
Review
Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein (PK) and circulates in plasma bound to high molecular weight kininogen. The zymogen is converted to PK by activated factor XII. PK drives multiple proteolytic reaction cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system and the alternative complement pathway. Here, we review the biochemistry and cell biology of PK and focus on recent in vivo studies that have established important functions of the protease in procoagulant and proinflammatory disease states. Targeting PK offers novel strategies not previously appreciated to interfere with thrombosis and vascular inflammation in a broad variety of diseases.
Topics: Animals; Aprotinin; Blood Coagulation; Bradykinin; Cerebral Hemorrhage; Complement System Proteins; Cysteine; Diabetic Retinopathy; Disulfides; Factor XIIa; Fibrinolysis; Hemostasis; Humans; Inflammation; Kallikrein-Kinin System; Kallikreins; Kinins; Mice; Oligonucleotides, Antisense; Peptides; Plasma Kallikrein; Protein Structure, Tertiary; Proteolysis; Renin-Angiotensin System; Signal Transduction; Thrombosis; Trypsin
PubMed: 23846131
DOI: 10.1160/TH13-03-0258 -
Frontiers in Physiology 2017Human plasma kallikrein-kinin system proteins are related to inflammation through bradykinin. In the proximity of its target cells, high molecular weight kininogen... (Review)
Review
Human plasma kallikrein-kinin system proteins are related to inflammation through bradykinin. In the proximity of its target cells, high molecular weight kininogen (H-kininogen) is the substrate of plasma kallikrein, which releases bradykinin from H-kininogen. Heparan sulfate proteoglycans (HSPGs) play a critical role in either recruiting kinin precursors from the plasma, or in the assembly of kallikrein-kinin system components on the cell surface. Furthermore, HSPGs mediate the endocytosis and activation of H-kininogen and plasma prekallikrein. In the presence of HSPGs (Chinese hamster ovary cell, CHO-K1, wild type cells) both heparin and heparan sulfate strongly inhibit the H-kininogen interaction with the cell membrane. H-kininogen is internalized in endosomal acidic vesicles in CHO-K1 but not in CHO-745 cells (mutant cells deficient in glycosaminoglycan biosynthesis). The endocytosis process is lipid raft-mediated and is dependent on caveolae. Both types of CHO cells do not internalize bradykinin-free H-kininogen. At pH 7.35, bradykinin is released from H-kininogen on the surface of CHO-745 cells only by serine proteases; however, in CHO-K1 cells either serine or cysteine proteases are found to be involved. The CHO-K1 cell lysate contains different kininogenases. Plasma prekallikrein endocytosis in CHO-K1 cells is independent of H-kininogen, and also prekallikrein is not internalized by CHO-745 cells. Plasma prekallikrein cleavage/activation is independent of glycosaminoglycans but plasma kallikrein formation is more specific on H-kininogen assembled on the cell surface through glycosaminoglycans. In this mini-review, the importance of HSPGs in the regulation of plasma kallikrein-kinin system proteins is shown.
PubMed: 28744223
DOI: 10.3389/fphys.2017.00481 -
Frontiers in Pharmacology 2021The occurrence and persistence of hepatic injury which arises from cell death and inflammation result in liver disease. The processes that lead to liver injury...
The occurrence and persistence of hepatic injury which arises from cell death and inflammation result in liver disease. The processes that lead to liver injury progression and resolution are still not fully delineated. The plasma kallikrein-kinin system (PKKS) has been shown to play diverse functions in coagulation, tissue injury, and inflammation, but its role in liver injury has not been defined yet. In this study, we have characterized the role of the PKKS at various stages of liver injury in mice, as well as the direct effects of plasma kallikrein on human hepatocellular carcinoma cell line (HepG2). Histological, immunohistochemical, and gene expression analyses were utilized to assess cell injury on inflammatory and fibrotic factors. Acute liver injury triggered by carbon tetrachloride (CCl) injection resulted in significant upregulation of the plasma kallikrein gene (Klkb1) and was highly associated with the high mobility group box 1 gene, the marker of cell death ( = 0.75, < 0.0005, = 7). In addition, increased protein expression of plasma kallikrein was observed as clusters around necrotic areas. Plasma kallikrein treatment significantly increased the proliferation of CCl-induced HepG2 cells and induced a significant increase in the gene expression of the thrombin receptor (protease activated receptor-1), interleukin 1 beta, and lectin-galactose binding soluble 3 (galectin-3) ( < 0.05, = 4). Temporal variations in the stages of liver fibrosis were associated with an increase in the mRNA levels of bradykinin receptors: beta 1 and 2 genes ( < 0.05; = 3-10). In conclusion, these findings indicate that plasma kallikrein may play diverse roles in liver injury, inflammation, and fibrosis, and suggest that plasma kallikrein may be a target for intervention in the states of liver injury.
PubMed: 34566641
DOI: 10.3389/fphar.2021.715111 -
Biological Chemistry Mar 2013Diabetic retinopathy (DR) occurs, to some extent, in most people with at least 20 years' duration of diabetes mellitus. The progression of DR to its sight-threatening... (Review)
Review
Diabetic retinopathy (DR) occurs, to some extent, in most people with at least 20 years' duration of diabetes mellitus. The progression of DR to its sight-threatening stages is usually associated with the worsening of underlying retinal vascular dysfunction and disease. The plasma kallikrein-kinin system (KKS) is activated during vascular injury, where it mediates important functions in innate inflammation, blood flow, and coagulation. Recent findings from human vitreous proteomics and experimental studies on diabetic animal models have implicated the KKS in contributing to DR. Vitreous fluid from people with advanced stages of DR contains increased levels of plasma KKS components, including plasma kallikrein (PK), coagulation factor XII, and high-molecular-weight kininogen. Both bradykinin B1 and B2 receptor isoforms (B1R and B2R, respectively) are expressed in human retina, and retinal B1R levels are increased in diabetic rodents. The activation of the intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening, and these responses are exacerbated in diabetic rats. Preclinical studies have shown that the administration of PK inhibitors and B1R antagonists to diabetic rats ameliorates retinal vascular hyperpermeability and inflammation. These findings suggest that components of plasma KKS are potential therapeutic targets for diabetic macular edema.
Topics: Blood Chemical Analysis; Diabetic Retinopathy; Humans; Kallikrein-Kinin System; Plasma; Retinal Neovascularization
PubMed: 23362193
DOI: 10.1515/hsz-2012-0316 -
European Journal of Medicinal Chemistry Mar 2020Plasma kallikrein (PKal) belongs to the family of trypsin-like serine proteases. The expression of PKal is associated with multiple physiological systems or pathways... (Review)
Review
Plasma kallikrein (PKal) belongs to the family of trypsin-like serine proteases. The expression of PKal is associated with multiple physiological systems or pathways such as coagulation pathway, platelet aggregation process, kallikrein-kinin system, renin-angiotensin system and complement pathway. On the basis of PKal's multiple physiological functions, it has been considered as a potential target for several diseases including hereditary angioedema, microvascular complications of diabetes mellitus and cerebrovascular disease. Up to now, many PKal inhibitors have been identified and a few of them have reached clinical trials or market. This review summarizes the development of small molecule and peptide PKal inhibitors having different scaffolds and discusses their structure-activity relationship and selectivity. We hope this review facilitates a comprehensive understanding of the types of PKal inhibitors developed to tackle different manifestations of PKal-associated diseases.
Topics: Animals; Catalytic Domain; Drug Discovery; Enzyme Inhibitors; Humans; Molecular Structure; Plasma Kallikrein; Protein Binding; Structure-Activity Relationship
PubMed: 32066009
DOI: 10.1016/j.ejmech.2020.112137 -
Cardiovascular & Hematological Agents... Jul 2009The plasma kallikrein-kinin system (KKS) plays a critical role in human physiology. The KKS encompasses coagulation factor XII (FXII), the complex of prekallikrein (PK)... (Review)
Review
The plasma kallikrein-kinin system (KKS) plays a critical role in human physiology. The KKS encompasses coagulation factor XII (FXII), the complex of prekallikrein (PK) and high molecular weight kininogen (HK). The conversion of plasma prekallikrein to kallikrein by the activated FXII and in response to numerous different stimuli leads to the generation of bradykinin (BK) and activated HK (HKa, an antiangiogenic peptide). BK is a proinflammatory peptide, a pain mediator and potent vasodilator, leading to robust accumulation of fluid in the interstitium. Systemic production of BK, HKa with the interplay between BK bound-BK receptors and the soluble form of HKa are key to angiogenesis and hemodynamics. KKS has been implicated in the pathogenesis of inflammation, hypertension, endotoxemia, and coagulopathy. In all these cases increased BK levels is the hallmark. In some cases, the persistent production of BK due to the deficiency of the blood protein C1-inhibitor, which controls FXII, is detrimental to the survival of the patients with hereditary angioedema (HAE). In others, the inability of angiotensin converting enzyme (ACE) to degrade BK leads to elevated BK levels and edema in patients on ACE inhibitors. Thus, the mechanisms that interfere with BK liberation or degradation would lead to blood pressure dysfunction. In contrast, anti-kallikrein treatment could have adverse effects in hemodynamic changes induced by vasoconstrictor agents. Genetic models of kallikrein deficiency are needed to evaluate the quantitative role of kallikrein and to validate whether strategies designed to activate or inhibit kallikrein may be important for regulating whole-body BK sensitivity.
Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Humans; Kallikrein-Kinin System; Kallikreins; Molecular Sequence Data; Plasma
PubMed: 19689262
DOI: 10.2174/187152509789105444