• Kallikrein–Kinin system
• fulminant myocarditis
• inducible nitric oxide synthase
• inflammatory
• nitric oxide

• National Natural Science Foundation of China

• Amino Acids/metabolism
• Animals
• Chemokines/metabolism
• Chemokines, CC
• Diabetes Mellitus, Type 2/complications
• Disease Models, Animal
• Down-Regulation
• Endothelial Cells/metabolism
• Humans
• Ligands
• Lysosome-Associated Membrane Glycoproteins/metabolism
• Mice
• Nitric Oxide Synthase Type III/genetics
• Nitric Oxide Synthase Type III/metabolism
• Obesity/genetics
• Oxides/metabolism
• Receptors, CCR10
• Receptors, Chemokine/metabolism
• Vascular Endothelial Growth Factor A/metabolism
• Wound Healing

• R01 DK109948 NIDDK NIH HHS
• R01 HL125356 NHLBI NIH HHS
• R01 HL142636 NHLBI NIH HHS
• R35 GM136228 NIGMS NIH HHS
• UL1 TR002003 NCATS NIH HHS
• P30 DK020572 NIDDK NIH HHS
• R35 GM139603 NIGMS NIH HHS
• UL1 RR029879 NCRR NIH HHS
• American Diabetes Association
• National Institutes of Health
• Patent and Trademark Office
• University of Illinois at Chicago
• CTSA

• Long non-coding RNA growth arrest specific transcript 5
• NF-ΚB
• microRNA-188-p
• myocardial ischemia-reperfusion injury
• smad2

• Animals
• Cells, Cultured
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Myocardial Reperfusion Injury/genetics
• Myocardial Reperfusion Injury/metabolism
• Myocardial Reperfusion Injury/pathology
• Myocytes, Cardiac/metabolism
• RNA, Small Nucleolar/genetics
• RNA, Small Nucleolar/metabolism
• Smad2 Protein/genetics
• Smad2 Protein/metabolism

The aim of the present study was to investigate the protective effects and mechanisms of KLK1 on aging-related prostate alterations and search clues about the application of KLK1 to the treatment of human BPH.

Thirty-six rats including 26 male wild-type SD rats and 10 transgenic rats were fed to 3- or 18-month-old and divided into three groups: young WTR (yWTR) as the control (n = 16), aged WTR (aWTR) (n = 10), and aged TGR (aTGR) (n = 10). The prostates of the three groups of rats (10 rats per group) were harvested to evaluate the levels of KLK1 expression, oxidative stress, fibrosis, and involved signaling pathways, such as NO/cGMP, COX-2/PTGIS/cAMP, and TGF-β1/RhoA/ROCK1, via quantitative PCR, Western blot, histological examinations, and ELISA. Moreover, the remaining 6 yWTRs were sacrificed to obtain primary prostate fibroblast and aortic endothelial cells, and a coculture system was built with the cells for the verification of above signaling pathways in vitro. And the direct effects of bradykinin on prostate cells were detected by MTT experiment. Prostate specimens of 47 patients (age from 48 to 92 years) undergoing BPH surgery were collected after approval. Histological examinations and KLK1 IHC were preformed to analyze the relationship between KLK1 expression and age and prostate fibrosis.

The human KLK1 gene only existed and was expressed in aTGR. The prostate of young rats expressed more KLK1 than the aged and the expression of KLK1 in prostate decreased with age in humans (r = −0.347, P = 0.018). Compared to the aWTR group, the yWTR and aTGR groups showed milder fibrosis, less oxidative stress, upregulated NO/cGMP, and COX-2/PTGIS/cAMP signaling pathways and inhibited TGF-β1/RhoA/ROCK1 signaling pathway. In the coculture system, KLK1 suppressed TGF-β1-mediated fibroblast-to-myofibroblast transdifferentiation via cleaving LMWK to produce the BK which upregulate eNOS expression and NO production in endothelial cells. BK not only slightly stimulated the proliferation ability of prostatic stromal cells but also upregulated iNOS and inhibited TGF-β1 expression in them.

KLK1 protects prostate from oxidative stress and fibrosis via amplified NO/cGMP signal in aged rats. The decrease of KLK1 expression with aging is laying the groundwork for the application of KLK1 to the treatment of human BPH. The current experimental data showed that the side effects of KLK1 on the prostate cell were not obvious.

• tissue kallikrein 1
• tissue inhibitors of matrix metalloproteinase 1
• myocardial infarction
• ischemia‑reperfusion injury
• angiogenesis
• oxidative stress

Myocardial ischemic injury is among the top 10 leading causes of death from cardiovascular diseases worldwide. Myocardial ischemia is caused mainly by coronary artery occlusion or obstruction. It usually occurs when the heart is insufficiently perfused, oxygen supply to the myocardium is reduced, and energy metabolism in the myocardium is abnormal. Pathologically, myocardial ischemic injury generates a large number of inflammatory cells, thus inducing a state of oxidative stress. This sharp reduction in the number of normal cells as a result of apoptosis leads to organ and tissue damage, which can be life-threatening. Therefore, effective methods for the treatment of myocardial ischemic injury and clarification of the underlying mechanisms are urgently required. Gaseous signaling molecules, such as NO, H₂S, H₂, and combined gas donors, have gradually become a focus of research. Gaseous signaling molecules have shown anti-apoptotic, anti-oxidative and anti-inflammatory effects as potential therapeutic agents for myocardial ischemic injury in a large number of studies. In this review, we summarize and discuss the mechanism underlying the protective effect of gaseous signaling molecules on myocardial ischemic injury.

• H2
• H2S
• NO
• gas co-dornor
• myocardial ischemia
• protecting mechanisms

• LCZ696
• NF-κB
• apoptosis
• diabetic cardiomyopathy
• inflammation
• oxidative stress

• cardiac regeneration
• cardioprotection
• omics data
• precision medicine
• stem cells

• PN-III-P2-2.1-PED-2016-1333 Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii

• ERK
• Fibrosis, Notch3
• Obstructive nephropathy
• TGFβ
• UUO model

• Adult
• Animals
• Cells, Cultured
• Chronic Disease
• Disease Models, Animal
• Epithelial Cells/cytology
• Epithelial Cells/metabolism
• Female
• Fibrosis/metabolism
• Gene Expression Regulation
• Humans
• Kidney Diseases/metabolism
• Kidney Diseases/pathology
• Kidney Tubules, Proximal/cytology
• Kidney Tubules, Proximal/metabolism
• MAP Kinase Signaling System/physiology
• Male
• Middle Aged
• Rats
• Rats, Sprague-Dawley
• Receptor, Notch3/metabolism
• Transforming Growth Factor beta/physiology
• Ureteral Obstruction/metabolism
• Ureteral Obstruction/pathology

The tissue kallikrein-kinin system (KKS) is an endogenous multiprotein metabolic cascade which is implicated in the homeostasis of the cardiovascular, renal and central nervous system. Human tissue kallikrein (KLK1) is a serine protease, component of the KKS that has been demonstrated to exert pleiotropic beneficial effects in protection from tissue injury through its anti-inflammatory, anti-apoptotic, anti-fibrotic and anti-oxidative actions. Mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs) constitute populations of well-characterized, readily obtainable multipotent cells with special immunomodulatory, migratory and paracrine properties rendering them appealing potential therapeutics in experimental animal models of various diseases. Genetic modification enhances their inherent properties. MSCs or EPCs are competent cellular vehicles for drug and/or gene delivery in the targeted treatment of diseases. KLK1 gene delivery using adenoviral vectors or KLK1 protein infusion into injured tissues of animal models has provided particularly encouraging results in attenuating or reversing myocardial, renal and cerebrovascular ischemic phenotype and tissue damage, thus paving the way for the administration of genetically modified MSCs or EPCs with the human tissue KLK1 gene. Engraftment of KLK1-modified MSCs and/or KLK1-modified EPCs resulted in advanced beneficial outcome regarding heart and kidney protection and recovery from ischemic insults. Collectively, findings from pre-clinical studies raise the possibility that tissue KLK1 may be a novel future therapeutic target in the treatment of a wide range of cardiovascular, cerebrovascular and renal disorders.

• Aged
• Cyclic Guanosine Monophosphate
• Erectile Dysfunction
• Fibrosis
• Gene Therapy
• Kallikrein 1

• Animals
• Cyclic GMP/metabolism
• Erectile Dysfunction/metabolism
• Erectile Dysfunction/physiopathology
• In Situ Nick-End Labeling
• Lim Kinases/metabolism
• Male
• Nitric Oxide Synthase Type III/metabolism
• Penile Erection/drug effects
• Penis/blood supply
• Rats
• Rats, Sprague-Dawley
• Rats, Transgenic
• Tissue Kallikreins/metabolism
• Transforming Growth Factor beta1/metabolism
• rho-Associated Kinases/metabolism

Transforming growth factor β (TGF-β) is a multifunctional cytokine that is synthesized by many types of cells and regulates the cell cycle. Increasing evidence has led to TGF-β receiving increased and deserved attention in recent years because it may play a potentially novel and critical role in the development and progression of myocardial fibrosis and the subsequent progress of ventricular remodeling (VR). Numerous studies have highlighted a crucial role of TGF-β in VR and suggest potential therapeutic targets of the TGF-β signaling pathways for VR. Changes in TGF-β activity may elicit anti-VR activity and may serve as a novel therapeutic target for VR therapy. This review we discusses the smad-dependent signaling pathway, such as TGF-β/Smads, TGF-β/Sirtuins, TGF-β/BMP, TGF-β/miRNAs, TGF-β/MAPK, and Smad-independent signaling pathway of TGF-β, such as TGF-β/PI3K/Akt, TGF-β/Rho/ROCK,TGF-β/Wnt/β-catenin in the cardiac fibrosis and subsequent progression of VR. Furthermore, agonists and antagonists of TGF-β as potential therapeutic targets in VR are also described.

• mechanism
• myocardial fibrosis
• targets
• transforming growth factor β
• ventricular remodeling

• cardiac remodeling
• myocardial infarction
• nitric oxide
• sleep restriction
• ubiquitin–proteasome system

The tissue kallikrein-related peptidase family (KLK) is a group of trypsin- and chymotrypsin-like serine proteases that share a similar homology to parent tissue kallikrein (KLK1). KLK1 is identified in heart and has anti-hypertrophic effects. However, whether other KLK family members play a role in regulating cardiac function remains unknown. In the present study, we demonstrated for the first time that KLK8 was expressed in myocardium. KLK8 expression was upregulated in left ventricle of cardiac hypertrophy models. Both intra-cardiac adenovirus-mediated and transgenic-mediated KLK8 overexpression led to cardiac hypertrophy in vivo. In primary neonatal rat cardiomyocytes, KLK8 knockdown inhibited phenylephrine (PE)-induced cardiomyocyte hypertrophy, whereas KLK8 overexpression promoted cardiomyocyte hypertrophy via a serine protease activity-dependent but kinin receptor-independent pathway. KLK8 overexpression increased epidermal growth factor (EGF) production, which was blocked by the inhibitors of serine protease. EGF receptor (EGFR) antagonist and EGFR knockdown reversed the hypertrophy induced by KLK8 overexpression. KLK8-induced cardiomyocyte hypertrophy was also significantly decreased by blocking the protease-activated receptor 1 (PAR1) or PAR2 pathway. Our data suggest that KLK8 may promote cardiomyocyte hypertrophy through EGF signaling- and PARs-dependent but a kinin receptor-independent pathway. It is implied that different KLK family members can subtly regulate cardiac function and remodeling.

Tissue kallikrein 1 (TK1) and tissue inhibitor of matrix metalloproteinase 1 (TIMP1) are important in inhibiting vascular smooth muscle cell (VSMC) proliferation and improving vascular remodeling, respectively. It was hypothesized that a combination of TK1 and TIMP1 genes, mediated by an adenovirus vector could augment or act in synergy to enhance the inhibitory effects. The promoter, mCMV carrying hTIMP1 cDNA was subcloned into pDC316-hTK1 to construct a recombinant plasmid carrying hTK1 and hTIMP1 genes. Subsequently, the double gene plasmid and adenovirus backbone plasmid were packaged into HEK293A cells. Gene transcription and protein expression were examined, respectively using reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting assays. VSMC proliferation was assessed using cell counting and methyl-thiazolyl-tetrazoliuin methods. The constructed plasmid containing hTK1 and hTIMP1 genes was correctly identified by means of PCR, double digestion and sequencing analysis. The co-expression vector, Ad-hTK1-hTIMP1 was successfully constructed and packaged into HEK293A cells. When VSMCs were transfected with the co-expression vector, the mRNA transcription and protein expression of hTK1 and hTIMP1 exhibited abundant expression in a concentration-dependent and time-dependent manner, independently. In conclusion, the co-expression vector synergistically inhibited the cell growth and proliferation induced by platelet-derived growth factor-BB compared with the single gene vector.

• Cardiac ischemia–reperfusion
• Cyclosporin A
• Mitochondria
• Tissue kallikrein

• Animals
• Cardiotonic Agents/pharmacology
• Peptidyl-Prolyl Isomerase F
• Cyclophilins/genetics
• Cyclophilins/metabolism
• Cyclosporine/pharmacology
• Gene Expression
• Heterozygote
• Homozygote
• Ischemic Postconditioning
• Male
• Mice
• Mice, Knockout
• Mitochondria, Heart/drug effects
• Mitochondria, Heart/metabolism
• Mitochondrial Membrane Transport Proteins/genetics
• Mitochondrial Membrane Transport Proteins/metabolism
• Mitochondrial Permeability Transition Pore
• Myocardial Ischemia/drug therapy
• Myocardial Ischemia/genetics
• Myocardial Ischemia/metabolism
• Myocardial Ischemia/pathology
• Myocardium/metabolism
• Myocardium/pathology
• Myocytes, Cardiac/cytology
• Myocytes, Cardiac/drug effects
• Myocytes, Cardiac/metabolism
• Oxidative Phosphorylation
• Rats
• Signal Transduction
• Tissue Kallikreins/deficiency
• Tissue Kallikreins/genetics
• Voltage-Dependent Anion Channel 1/genetics
• Voltage-Dependent Anion Channel 1/metabolism

The tissue kallikrein-kinin system exerts a wide spectrum of biological activities in the cardiovascular, renal and central nervous systems. Tissue kallikrein-kinin modulates the proliferation, viability, mobility and functional activity of certain stem cell populations, namely mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), mononuclear cell subsets and neural stem cells. Stimulation of these stem cells by tissue kallikrein-kinin may lead to protection against renal, cardiovascular and neural damage by inhibiting apoptosis, inflammation, fibrosis and oxidative stress and promoting neovascularization. Moreover, MSCs and EPCs genetically modified with tissue kallikrein are resistant to hypoxia- and oxidative stress-induced apoptosis, and offer enhanced protective actions in animal models of heart and kidney injury and hindlimb ischemia. In addition, activation of the plasma kallikrein-kinin system promotes EPC recruitment to the inflamed synovium of arthritic rats. Conversely, cleaved high molecular weight kininogen, a product of plasma kallikrein, reduces the viability and vasculogenic activity of EPCs. Therefore, kallikrein-kinin provides a new approach in enhancing the efficacy of stem cell therapy for human diseases.

• Tissue kallikrein
• Plasma kallikrein
• Kinin
• Mesenchymal stem cells
• Endothelial progenitor cells
• Neural stem cells
• Heart
• Kidney
• Brain

• R01 HL029397 NHLBI NIH HHS
• R01 HL044083 NHLBI NIH HHS
• R01 HL118516 NHLBI NIH HHS

Tissue kallikrein (TK) has been shown to provide cardiovascular and cerebrovascular protective effects in animal models. The aim of this study was to investigate the relationship of plasma TK levels with the presence and severity of coronary artery disease (CAD) in the Chinese.

The study involved 898 consecutive CAD patients and 905 ethnically and geographically matched controls. CAD was angiographically confirmed in all the patients, and the severity of CAD was expressed by the number of affected vessel and coronary artery stenosis scores. Plasma TK levels were measured using an enzyme-linked immunosorbent assay.

Plasma TK levels were significantly higher in CAD patients than controls (0.347±.082 vs. 0.256±0.087 mg/L, P<0.001), and elevated plasma TK levels were directly associated with a higher risk of CAD (OR = 3.49, 95% CI 2.90–4.19). One-way ANOVA and multivariable stepwise linear regression analysis demonstrated that TK levels were negatively associated with the severity of CAD according to vessel scores (P<0.001) and stenosis scores (r = −0.211, p<0.001).

Our findings suggest that higher levels of TK in plasma are associated with the presence of CAD and are a predictor of mild coronary arteriosclerosis.

• Aged
• Animals
• Arteriosclerosis/blood
• Arteriosclerosis/pathology
• Blood Pressure
• Coronary Angiography
• Coronary Artery Disease/blood
• Coronary Artery Disease/pathology
• Female
• Humans
• Hypertension/blood
• Hypertension/pathology
• Male
• Middle Aged
• Risk Factors
• Severity of Illness Index
• Tissue Kallikreins/blood

• Animals
• Apoptosis
• Capillaries/pathology
• Cardiomegaly/physiopathology
• Cardiomegaly/prevention & control
• Fibrillar Collagens/metabolism
• Isoproterenol
• Kallikreins/metabolism
• Kinins/metabolism
• Male
• Myocardium/pathology
• Neovascularization, Physiologic
• Physical Conditioning, Animal
• Rats, Wistar
• Sympathetic Nervous System/physiopathology

• Animals
• Cardiovascular Agents/therapeutic use
• Cardiovascular Diseases/drug therapy
• Cardiovascular Diseases/enzymology
• Cardiovascular Diseases/genetics
• Cardiovascular Diseases/physiopathology
• Genetic Predisposition to Disease
• Genetic Variation
• Humans
• Kallikreins/genetics
• Kallikreins/metabolism
• Kidney Diseases/drug therapy
• Kidney Diseases/enzymology
• Kidney Diseases/genetics
• Kidney Diseases/physiopathology
• Kinins/genetics
• Kinins/metabolism
• Phenotype
• Renal Agents/therapeutic use
• Signal Transduction

Cell senescence is central to a large body of age related pathology, and accordingly, cardiomyocytes senescence is involved in many age related cardiovascular diseases. In consideration of that, delaying cardiomyocytes senescence is of great importance to control clinical cardiovascular diseases. Previous study indicated that bradykinin (BK) protected endothelial cells from senescence induced by oxidative stress. However, the effects of bradykinin on cardiomyocytes senescence remain to be elucidated. In this study, we investigated the effect of bradykinin on H₂O₂-induced H9C2 cells senescence.

Bradykinin pretreatment decreased the senescence induced by H₂O₂ in cultured H9C2 cells in a dose dependent manner. Interestingly, 1 nmol/L of BK almost completely inhibited the increase in senescent cell number and p21 expression induced by H₂O₂. Since H₂O₂ induces senescence through superoxide-induced DNA damage, we also observed the DNA damage by comet assay, and BK markedly reduced DNA damage induced by H₂O₂, and moreover, BK treatment significantly prevented reactive oxygen species (ROS) production in H9C2 cells treated with H₂O₂. Importantly, when co-incubated with bradykinin B2 receptor antagonist HOE-140 or eNOS inhibitor N-methyl-L-arginine acetate salt (L-NAME), the protective effects of bradykinin on H9C2 senescence were totally blocked. Furthermore, BK administration significantly prevented the increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity characterized by increased ROS generation and gp91 expression and increased translocation of p47 and p67 to the membrane and the decrease in superoxide dismutase (SOD) activity and expression induced by H₂O₂ in H9C2 cells, which was dependent on BK B2 receptor mediated nitric oxide (NO) release.

Bradykinin, acting through BK B2 receptor induced NO release, upregulated antioxidant Cu/Zn-SOD and Mn-SOD activity and expression while downregulating NADPH oxidase activity and subsequently inhibited ROS production, and finally protected against cardiomyocytes senescence induced by oxidative stress.

• Animals
• Blotting, Western
• Bradykinin/analogs & derivatives
• Bradykinin/pharmacology
• Bradykinin B2 Receptor Antagonists
• Cell Line
• Cellular Senescence/drug effects
• Comet Assay
• DNA Damage/drug effects
• Dose-Response Relationship, Drug
• Enzyme Inhibitors/adverse effects
• Flow Cytometry
• Hydrogen Peroxide/pharmacology
• Myocytes, Cardiac/cytology
• Myocytes, Cardiac/drug effects
• Myocytes, Cardiac/metabolism
• NADPH Oxidases/metabolism
• NG-Nitroarginine Methyl Ester/pharmacology
• Nitric Oxide/metabolism
• Nitric Oxide Synthase/antagonists & inhibitors
• Nitric Oxide Synthase/metabolism
• Oxidants/pharmacology
• Oxidation-Reduction/drug effects
• Oxidative Stress/drug effects
• Rats
• Reactive Oxygen Species/metabolism
• Receptor, Bradykinin B2/metabolism
• Superoxide Dismutase/metabolism

• radiation-induced heart disease
• kallikrein-kinin system
• bradykinin

• Animals
• Antigens, CD/analysis
• Antigens, Differentiation, Myelomonocytic/analysis
• Blotting, Western
• CD2 Antigens/analysis
• Gene Expression/radiation effects
• Heart/physiopathology
• Heart/radiation effects
• Immunohistochemistry
• In Vitro Techniques
• Kallikrein-Kinin System
• Kininogens/deficiency
• Kininogens/genetics
• MAP Kinase Signaling System/radiation effects
• Mitochondrial Swelling/radiation effects
• Mitogen-Activated Protein Kinase 1/metabolism
• Mitogen-Activated Protein Kinase 3/metabolism
• Myocarditis/etiology
• Myocarditis/genetics
• Myocarditis/metabolism
• Myocardium/metabolism
• Myocardium/pathology
• NADPH Oxidases/genetics
• Phosphorylation/radiation effects
• Radiation Injuries, Experimental/complications
• Rats
• Rats, Inbred BN
• Receptor, Bradykinin B2/genetics
• Reverse Transcriptase Polymerase Chain Reaction

• R01 CA148679 NCI NIH HHS
• CA148679 NCI NIH HHS
• R37 CA071382 NCI NIH HHS
• R01 CA071382 NCI NIH HHS
• CA71382 NCI NIH HHS

• Animals
• Endothelin-1/antagonists & inhibitors
• Heart Diseases/etiology
• Humans
• Mast Cells/physiology
• Radiation Injuries, Experimental/etiology
• Radiotherapy/adverse effects
• Thoracic Neoplasms/radiotherapy

• R01 CA148679 NCI NIH HHS
• CA148679 NCI NIH HHS

• R01 CA071382 NCI NIH HHS
• R01 CA083719 NCI NIH HHS
• R01 CA148679 NCI NIH HHS
• R37 CA071382 NCI NIH HHS

• Animals
• Antibodies, Monoclonal/therapeutic use
• CD47 Antigen/physiology
• Female
• Immunologic Factors/therapeutic use
• Liver/metabolism
• Liver/surgery
• Male
• Mice
• Mice, Inbred C57BL
• Recovery of Function
• Reperfusion Injury/etiology
• Reperfusion Injury/metabolism
• Reperfusion Injury/therapy
• Signal Transduction/physiology
• Thrombospondin 1/physiology

• HL54390 NHLBI NIH HHS
• Z01 SC009172-04 Intramural NIH HHS
• R01 HL054390 NHLBI NIH HHS
• R01 GM057573 NIGMS NIH HHS
• Z01 SC009174-04 Intramural NIH HHS
• R56 HL054390 NHLBI NIH HHS
• GM57573 NIGMS NIH HHS