Matrix metalloproteinase-10 effectively reduces infarct size in experimental stroke by enhancing fibrinolysis via a thrombin-activatable fibrinolysis inhibitor-mediated mechanism

BACKGROUND: The fibrinolytic and matrix metalloproteinase (MMP) systems cooperate in thrombus dissolution and extracellular matrix proteolysis. The plasminogen/plasmin system activates MMPs, and some MMPs have been involved in the dissolution of fibrin by targeting fibrin(ogen) directly or by collaborating with plasmin. MMP-10 has been implicated in inflammatory/thrombotic processes and vascular integrity, but whether MMP-10 could have a profibrinolytic effect and represent a promising thrombolytic agent is unknown. METHODS AND RESULTS: The effect of MMP-10 on fibrinolysis was studied in vitro and in vivo, in MMP-10-null mice (Mmp10(-/-)), with the use of 2 different murine models of arterial thrombosis: laser-induced carotid injury and ischemic stroke. In vitro, we showed that MMP-10 was capable of enhancing tissue plasminogen activator-induced fibrinolysis via a thrombin-activatable fibrinolysis inhibitor inactivation-mediated mechanism. In vivo, delayed fibrinolysis observed after photochemical carotid injury in Mmp10(-/-) mice was reversed by active recombinant human MMP-10. In a thrombin-induced stroke model, the reperfusion and the infarct size in sham or tissue plasminogen activator-treated animals were severely impaired in Mmp10(-/-) mice. In this model, administration of active MMP-10 to wild-type animals significantly reduced blood reperfusion time and infarct size to the same extent as tissue plasminogen activator and was associated with shorter bleeding time and no intracranial hemorrhage. This effect was not observed in thrombin-activatable fibrinolysis inhibitor-deficient mice, suggesting thrombin-activatable fibrinolysis inhibitor inactivation as one of the mechanisms involved in the MMP-10 profibrinolytic effect. CONCLUSIONS: A novel profibrinolytic role for MMP-10 in experimental ischemic stroke is described, opening new pathways for innovative fibrinolytic strategies in arterial thrombosis

Relationship between apolipoprotein(a) size polymorphism and coronary heart disease in overweight subjects

BACKGROUND: Overweight is associated with an increased cardiovascular risk which is only partially explained by conventional risk factors. The objective of this study was to evaluate lipoprotein(a) [Lp(a)] plasma levels and apolipoprotein(a) [apo(a)] phenotypes in relation to coronary heart disease (CHD) in overweight subjects. METHODS: A total of 275 overweight (BMI ≥ 27 kg/m(2)) subjects, of which 155 had experienced a CHD event, 337 normal weight subjects with prior CHD and 103 CHD-free normal weight subjects were enrolled in the study. Lp(a) levels were determined by an ELISA technique and apo(a) isoforms were detected by a high-resolution immunoblotting method. RESULTS: Lp(a) levels were similar in the three study groups. Overweight subjects with CHD had Lp(a) concentrations significantly higher than those without [median (interquartile range): 20 (5–50.3) versus 12.6 (2.6–38.6) mg/dl, P < 0.05]. Furthermore, overweight subjects with CHD showed a higher prevalence of low molecular weight apo(a) isoforms than those without (55.5% versus 40.8%, P < 0.05) and with respect to the control group (55.5% versus 39.8%, P < 0.05). Stepwise regression analysis showed that apo(a) phenotypes, but not Lp(a) levels, entered the model as significant independent predictors of CHD in overweight subjects. CONCLUSIONS: Our data indicate that small-sized apo(a) isoforms are associated with CHD in overweight subjects. The characterization of apo(a) phenotypes might serve as a reliable biomarker to better assess the overall CHD risk of each subject with elevated BMI, leading to more intensive treatment of modifiable cardiovascular risk factors

Molecular analysis of afibrinogenemic mutations caused by a homozygous FGA1238 bp deletion, and a compound heterozygous FGA1238 bp deletion and novel FGA c.54+3A>C substitution

We identified two afibrinogenemic girls in two Japanese families and performed molecular analysis to clarify the mechanisms of fibrinogen defects. Genetic analyses were performed by PCR amplification of the fibrinogen gene and DNA sequence analysis. To analyze the mechanisms of mature fibrinogen defects in plasma, we cloned minigenes from the proposita's PCR-amplified DNA, transfected them into CHO cells, and sequenced the cDNA amplified with the RT reaction followed by PCR. Sequence analyses indicated that one was caused by a homozygous 1238 bp deletion of the fibrinogen A alpha-chain gene (FGA Delta 1238) and the other was a compound heterozygous FGA Delta 1238 and novel FGA c.54+3A > C substitution. The minigene corresponding to FGA Delta 1238 generates two aberrant mRNAs, both of which may induce a frameshift and terminate prematurely. In contrast, the minigene corresponding to FGA c.54+3A > C generates two aberrant mRNAs, one of which may induce a frameshift and terminate prematurely, and the other uses a cryptic 5' splice site in exon 1, resulting in the deletion of six amino acids in signal peptides. Molecular analyses of both genetic variants suggest that the lack of a mature A alpha-chain, impaired assembly, and/or secretion of the fibrinogen molecule may lead to afibrinogenemia.ArticleINTERNATIONAL JOURNAL OF HEMATOLOGY. 96(1):39-46 (2012)journal articl

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe