Abstract 2316: Myocardial PAI-1 Over-expression Mediates Graft Sclerosis in Cardiac Transplant Recipients with Idiopathic Dilated Cardiomyopathy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Seyedhossein Aharinejad ◽  
Katharina Krenn ◽  
Romana Schäfer ◽  
Andreas Zuckermann ◽  
Patrick Paulus ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Plasminogen Activator ◽  
Cardiac Transplantation ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Vascular Endothelial ◽  
Collagen Deposition ◽  
Post Transplant ◽  
Pai 1

Idiopathic dilated cardiomyopathy (DCM) is associated with reduced myocardial vascular density and increased collagen deposition with subsequent myocardial fibrosis and heart failure. The urokinase plasminogen activator (uPA)/plasminogen activator inhibitor (PAI) system plays an important role in extracellular matrix homeostasis as well as in preserving the integrity of the vascular endothelial cell (EC) intimal layer and EC regeneration, proliferation and motility. However, the involvement of the uPA/PAI system in DCM and graft remodeling following cardiac transplantation remains unclear. Gene expression of uPA, the uPA receptor uPAR and PAI-1 was examined in left ventricular (LV) biopsies of explanted hearts in 24 ischemic cardiomyopathy (ICM) and 60 DCM patients and 12 controls by real time RT-PCR and Western blotting. Vascular endothelial growth factor (VEGF) and uPA/PAI interplay was examined in stimulated DCM and ICM myocardium in vitro. Expression of uPA and PAI-1 mRNA was evaluated in endomyocardial biopsies (EMB) at 1, 2, 3, 4, 7, 12, 24 and 52 weeks post-transplant. The mRNA levels of uPA and uPAR were unchanged in both ICM and DCM patients compared to controls. PAI-1 mRNA and protein were up-regulated in DCM compared to ICM and controls (p<0.01). Active and inactive uPA protein was down-regulated in DCM and ICM compared to controls (p<0.05). VEGF stimulation in vitro did not affect uPA, uPAR or PAI-1 expression. Following transplantation, PAI-1 expression returned to baseline control levels in EMB from both patient groups, although PAI-1 expression increased at 24 and 52 weeks post-transplant in DCM patients (p<0.01 compared to post-transplant weeks 6 and 12). These data indicate a significant PAI-1 up-regulation associated with uPA down-regulation in DCM, independent of VEGF, which was temporarily corrected by cardiac transplantation. However, recurring up-regulation of myocardial PAI-1 levels at 6 and 12 months post-transplant suggest a persistent PAI-1-related molecular pathology in DCM. We have previously shown increased endothelin-1 expression and collagen deposition in grafts of DCM patients at 1 year post-transplant. The present data point to a previously unknown role of PAI-1 in mediating graft sclerosis.

scholarly journals Cardiac mitofusin-1 is reduced in non-responding patients with idiopathic dilated cardiomyopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yung Ting Hsiao ◽  
Ippei Shimizu ◽  
Takayuki Wakasugi ◽  
Yohko Yoshida ◽  
Ryutaro Ikegami ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Multidisciplinary Treatment ◽  
Left Ventricular ◽  
In Vitro Studies ◽  
Neonatal Rat ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Heart Failure Patients ◽  
Mitofusin 1

AbstractPrognosis of severe heart failure remains poor. Urgent new therapies are required. Some heart failure patients do not respond to established multidisciplinary treatment and are classified as “non-responders”. The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Mitofusin-1 (Mfn1), a mitochondrial fusion protein, is significantly reduced in non-responding patients. This study aimed to elucidate the role of Mfn1 in the failing heart. Twenty-two idiopathic dilated cardiomyopathy (IDCM) patients who underwent endomyocardial biopsy of intraventricular septum were included. Of the 22 patients, 8 were non-responders (left ventricular (LV) ejection fraction (LVEF) of < 10% improvement at late phase follow-up). Electron microscopy (EM), quantitative PCR, and immunofluorescence studies were performed to explore the biological processes and molecules involved in failure to respond. Studies in cardiac specific Mfn1 knockout mice (c-Mfn1 KO), and in vitro studies with neonatal rat ventricular myocytes (NRVMs) were also conducted. A significant reduction in mitochondrial size in cardiomyocytes, and Mfn1, was observed in non-responders. A LV pressure overload with thoracic aortic constriction (TAC) c-Mfn1 KO mouse model was generated. Systolic function was reduced in c-Mfn1 KO mice, while mitochondria alteration in TAC c-Mfn1 KO mice increased. In vitro studies in NRVMs indicated negative regulation of Mfn1 by the β-AR/cAMP/PKA/miR-140-5p pathway resulting in significant reduction in mitochondrial respiration of NRVMs. The level of miR140-5p was increased in cardiac tissues of non-responders. Mfn1 is a biomarker of heart failure in non-responders. Therapies targeting mitochondrial dynamics and homeostasis are next generation therapy for non-responding heart failure patients.

Activated Protein C Increases Fibrin Clot Lysis by Neutralization of Plasminogen Activator Inhibitor No Evidence for a Cofactor Role of Protein S

1988 ◽  
Vol 60 (02) ◽  
pp. 328-333 ◽  
Author(s):  
N J de Fouw ◽  
Y F de Jong ◽  
F Haverkate ◽  
R M Bertina
Keyword(s):  
Plasminogen Activator ◽  
Protein C ◽  
Blood Platelets ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Tissue Type ◽  
Clot Lysis ◽  
Activator Inhibitor ◽  
Pai 1

summaryThe effect of purified human activated protein G (APC) on fibrinolysis was studied using a clot iysis system consisting of purified glu-plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor (released from endothelial cells or blood platelets), fibrinogen, 125T-fibrinogen and thrombin. All proteins were of human origin.In this system APC could increase fibrinolysis in a dose dependent way, without affecting fibrin formation or fibrin crosslinking. However, this profibrinolytic effect of APC could only be observed when plasminogen activator inhibitor (PAI-l) was present. The effect of APC was completely quenched by pretreatment of APC with anti-protein C IgG or di-isopropylfluorophosphate. Addition of the cofactors of APC:protein S, Ca2+-ions and phospholipid-alone or in combination did not enhance the profibrinolytic effect of APC. These observations indicate that human APC can accelerate in vitro clot lysis by the inactivation of PAI-1 activity. However, the neutralization of PAI-1 by APC is independent of the presence or absence of protein S, phospholipid and Ca2+-ions.

The Roles of α2-Antiplasmin and Plasminogen Activator Inhibitor 1 (PAI-1) in the Inhibition of Clot Lysis

1993 ◽  
Vol 70 (02) ◽  
pp. 301-306 ◽  
Author(s):  
Linda A Robbie ◽  
Nuala A Booth ◽  
Alison M Croll ◽  
Bruce Bennett
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Dependent Inhibition ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe relative importance of the two major inhibitors of fibrinolysis, α2-antiplasmin (α2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified α2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to α2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 × 108/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, α2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of α2-AP, in such situations.

Localization of a Vitronectin Binding Region of Plasminogen Activator Inhibitor-1

1995 ◽  
Vol 73 (05) ◽  
pp. 829-834 ◽  
Author(s):  
Jaya Padmanabhan ◽  
David C Sane
Keyword(s):  
Binding Site ◽  
Plasminogen Activator ◽  
Inhibitory Activity ◽  
Plasminogen Activator Inhibitor ◽  
Structural Homology ◽  
Binding Region ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe PAI-1 binding site for VN was studied using two independent methods. PAI-1 was cleaved by Staph V8 protease, producing 8 fragments, only 2 of which bound to [125I]-VN. These fragments were predicted to overlap between residues 91-130. Since PAI-2 has structural homology to PAI-1, but does not bind to vitronectin, chimeras of PAI-1 and PAI-2 were constructed. Four chimeras, containing PAI-1 residues 1-70,1-105,1-114, and 1-167 were constructed and expressed in vitro. PAI-1, PAI-2, and all of the chimeras retained inhibitory activity for t-PA, but only the chimera containing PAI-1 residues 1-167 formed a complex with VN. Together, these results predict that the VN binding site of PAI-1 is between residues 115-130.

In Vitro Clot Lysis as a Potential Indicator of Thrombus Resistance to Fibrinolysis – Study in Healthy Subjects and Correlation with Blood Fibrinolytic Parameters

1997 ◽  
Vol 77 (04) ◽  
pp. 725-729 ◽  
Author(s):  
Mario Colucci ◽  
Silvia Scopece ◽  
Antonio V Gelato ◽  
Donato Dimonte ◽  
Nicola Semeraro
Keyword(s):  
Plasminogen Activator ◽  
Clot Lysis ◽  
Individual Response ◽  
Plasminogen Activator Inhibitor 1 ◽  
Autologous Plasma ◽  
Wide Range ◽  
Blood Clots ◽  
Physiological Variations ◽  
Pai 1

SummaryUsing an in vitro model of clot lysis, the individual response to a pharmacological concentration of recombinant tissue plasminogen activator (rt-PA) and the influence on this response of the physiological variations of blood parameters known to interfere with the fibrinolytic/thrombolytic process were investigated in 103 healthy donors. 125I-fibrin labelled blood clots were submersed in autologous plasma, supplemented with 500 ng/ml of rt-PA or solvent, and the degree of lysis was determined after 3 h of incubation at 37° C. Baseline plasma levels of t-PA, plasminogen activator inhibitor 1 (PAI-1), plasminogen, α2-anti-plasmin, fibrinogen, lipoprotein (a), thrombomodulin and von Willebrand factor as well as platelet and leukocyte count and clot retraction were also determined in each donor. rt-PA-induced clot lysis varied over a wide range (28-75%) and was significantly related to endogenous t-PA, PAI-1, plasminogen (p <0.001) and age (p <0.01). Multivariate analysis indicated that both PAI-1 antigen and plasminogen independently predicted low response to rt-PA. Surprisingly, however, not only PAI-1 but also plasminogen was negatively correlated with rt-PA-ginduced clot lysis. The observation that neutralization of PAI-1 by specific antibodies, both in plasma and within the clot, did not potentiate clot lysis indicates that the inhibitor, including the platelet-derived form, is insufficient to attenuate the thrombolytic activity of a pharmacological concentration of rt-PA and that its elevation, similarly to the elevation of plasminogen, is not the cause of clot resistance but rather a coincident finding. It is concluded that the in vitro response of blood clots to rt-PA is poorly influenced by the physiological variations of the examined parameters and that factors other than those evaluated in this study interfere with clot dissolution by rt-PA. In vitro clot lysis test might help to identify patients who may be resistant to thrombolytic therapy.

scholarly journals Vitamin D Status in Children with Idiopathic Dilated Cardiomyopathy

2021 ◽  
Vol 11 (01) ◽  
pp. e120-e124
Author(s):  
Duaa M. Raafat ◽  
Osama M. EL-Asheer ◽  
Amal A. Mahmoud ◽  
Manal M. Darwish ◽  
Naglaa S. Osman
Keyword(s):  
Vitamin D ◽  
Serum Level ◽  
Dilated Cardiomyopathy ◽  
Smooth Muscles ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Vitamin D Receptors ◽  
Left Ventricular Dimensions ◽  
And Function ◽  
Ventricular Dimensions

AbstractDilated cardiomyopathy (DCM) is the third leading cause of heart failure in pediatrics. The exact etiology of DCM is unknown in more than half of the cases. Vitamin D receptors are represented in cardiac muscles, endothelium, and smooth muscles of blood vessels suggesting that vitamin D could have a vital cardioprotective function. This study aimed to assess serum level of vitamin D in children with idiopathic DCM and to correlate the serum level of vitamin D with the left ventricular dimensions and function. This study is a descriptive cross-sectional single-center study, includes 44 children of both sexes, diagnosed as idiopathic DCM. Serum level of vitamin D was assessed and correlated with the left ventricular dimensions and function. Mean age of studied children was 6.08 ± 4.4 years. Vitamin D deficiency was found in 90.9% of children with idiopathic DCM with a mean level 13.48 ng/mL. There was a negative correlation between vitamin D level and fraction shortening and left ventricular end-diastolic diameter in children with DCM. Vitamin D level is not only significantly low in children with idiopathic DCM but it is also significantly correlated with the degree of left ventricular dysfunction.

Sign in / Sign up

Export Citation Format

Share Document