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Introduction Atherosclerosis is one of the major contributing factors for acute coronary syndrome (Gotlieb 2005), during which plaque builds up in the vascular lumen and either narrows blood vessels or [...], Paraoxanase-1 (PON1) is an HDL-associated enzyme that contributes to the antioxidant and antiatherosclerotic properties of HDL. Lack of PON1 results in dysfunctional HDL. HHcy is a risk factor for cardiovascular disorders, and instigates vascular dysfunction and ECM remodeling. Although studies have reported HHcy during atherosclerosis, the exact mechanism is unclear. Here, we hypothesize that dysfunctional HDL due to lack of PON1 contributes to endothelial impairment and atherogenesis through HHcy-induced ECM re-modeling. To verify this hypothesis, we used C57BL6/J and PON1 knockout mice (KO) and fed them an atherogenic diet. The expression of Akt, ADMA, and DDAH, as well as endothelial gap junction proteins such as Cx-37 and Cx-40 and eNOS was measured for vascular dysfunction and inflammation. We observed that cardiac function was decreased and plasma Hcy levels were increased in PON1 KO mice fed the atherogenic diet compared with the controls. Expression of Akt, eNOS, DDAH, Cx-37, and Cx-40 was decreased, and the expression of MMP-9 andADMA was increased in PON1 KO mice fed an atherogenic diet compared with the controls. Our results suggest that HHcy plays an intricate role in dysfunctional HDL, owing to the lack of PON1. This contributes to vascular endothelial impairment and atherosclerosis through MMP-9-induced vascular remodeling. Key words: atherosclerosis, homocysteine, Akt, eNOS, Cx-37 and--40, MMP-9. La paraoxanase 1 (PON1) est une enzyme associee aux HDL qui contribue a leurs proprietes antioxydantes et antiatherosclerosantes. De fait, un manque de PON1 est associe a des HDL dysfonctionnelles. Par ailleurs, l'hyperhomocysteinemie (HHcy) est un facteur de risque des troubles cardiovasculaires qui entraine des dysfonctions vasculaires et le remodelage de la matrice extracellulaire. Bien que des etudes aient fait etat d'une association entre l'HHcy et l'atherosclerose, le mecanisme exact n'a pas ete elucide. Dans les presents travaux, nous posons l'hypothese selon laquelle des HDL dysfonctionnelles en raison d'un deficit de PON1 contribuent a l'affaiblissement de l'endothelium et a l'atherogenese par un remodelage de la matrice extracellulaire entraine par l'HHcy. En vue de verifier cette hypothese, nous avons utilise des souris <> C57BL6/J et PON1 et leur avons administre un regime alimentaire atherosclerosant. Les expressions d'Akt, de la dimethylarginine asymetrique (ADMA), de la dimethylarginine dimethylaminohydrolase (DDAH), de proteines de jonctions gap endotheliales comme les connexines 37 et 40 ainsi que de la NO synthase endotheliale (eNOS) ont ete mesurees a l'egard de la dysfonction vasculaire et l'inflammation. Nous avons observe que la fonction cardiaque etait alteree et que les taux d'Hcy etaient augmentes davantage chez les souris <> PON1 auxquelles un regime alimentaire atherosclerosant etait administre que dans le groupe temoin. De plus, les expressions d'Akt, de la eNOS, de la DDAH et des connexines-37 et 40 etaient diminuees et les expressions de la metalloproteinase matricielle 9 (MMP-9) et de la ADMA etaient augmentees, et ce, davantage chez les souris <> PON1 auxquelles un regime alimentaire atherosclerosant etait administre que dans le groupe temoin. Nos resultats laissent entendre que l'HHcy jouerait un role complexe dans le dysfonctionnement des HDL entraine par un deficit en PON1, ce qui contribuerait a l'affaiblissement de l'endothelium vasculaire et a l'atherosclerose causes pour leur part par un remodelage vasculaire induit par la MMP-9. [Traduit par la Redaction] Mots-cles: atherosclerose, homocysteine, Akt, eNOS, connexines 37 et 40, MMP-9.

Introduction Homocysteine (Hcy), a sulfhydryl amino acid derived from methionine, has been widely identified as a risk factor in numerous disease states. Hyperhomocysteinemia (HHcy), demonstrating plasma Hcy levels > 15 [...], Introduction: Hyperhomocysteinemia (HHcy) is associated with inflammatory diseases and is known to increase the production of reactive oxygen species (ROS), matrix metalloproteinase (MMP)-9, and inducible nitric oxide synthase, and to decrease endothelial nitric oxide production. However, the impact of HHcy on macrophage phenotype differentiation is not well-established. It has been documented that macrophages have 2 distinct phenotypes: the 'classically activated/destructive' (M1), and the 'alternatively activated/constructive' (M2) subtypes. We hypothesize that HHcy increases M1 macrophage differentiation through extracellular matrix metalloproteinase inducer (EMMPRIN), a known inducer of matrix metalloproteinases. Methods: murine J774A.1 and Raw 264.7 macrophages were treated with 100 and 500 µmol/L Hcy, respectively, for 24 h. Samples were analyzed using Western blotting and immunocytochemistry. Results: Homocysteine treatment increased cluster of differentiation 40 (CD40; M1 marker) in J774A.1 and Raw 264.7 macrophages. MMP-9 was induced in both cell lines. EMMPRIN protein expression was also increased in both cell lines. Blocking EMMPRIN function by pre-treating cells with anti-EMMPRIN antibody, with or without Hcy, resulted in significantly lower expression of CD40 in both cell lines by comparison with the controls. A DCFDA assay demonstrated increased ROS production in both cell lines with Hcy treatment when compared with the controls. Conclusion: Our results suggest that HHcy results in an increase of the M1 macrophage phenotype. This effect seems to be at least partially mediated by EMMPRIN induction. Key words: macrophage, M1, homocysteine, MMP-9, EMMPRIN, ROS. Introduction: L'hyperhomocysteinemie est associee aux maladies inflammatoires, et on sait qu'elle entrame une augmentation de la production de derives reactifs de l'oxygene, de la metalloproteinase matricielle-9 (MMP-9) et de iNOS ainsi qu'une reduction de la production de NO par l'endothelium. Cependant, les repercussions de l'hyperhomocysteinemie sur la differenciation du phenotype des macrophages n'ont pas ete bien etablies. On a documente que les macrophages disposent de deux phenotypes distincts: les sous-types M1 (<< actives par la voie classique/destructeurs >>) et M2 (<< actives par la voie alterne/ constructeurs >>). Nous avons formule l'hypothese selon laquelle l'hyperhomocysteinemie entrame une augmentation de la differenciation des macrophages M1 par l'EMMPRIN, un inducteur connu des metalloproteinases matricielles. Methodologie: Des macrophages murins J774A.1 et Raw 264.7 ont ete traites pendant 24 heures au moyen d'homocysteine a 100 et a 500 µmol/L, respectivement. Les echantillons ont ete analyses a l'aide de techniques de Western blot et d'immunocytochimie. Resultats: Le traitement par l'homocysteine a entrame une augmentation de CD40 (un marqueur du sous-type M1) dans les macrophages J774A.1 et Raw 264.7. La production de MMP-9 a ete induite dans les deux lignees cellulaires. L'expression de la proteine EMMPRIN a aussi augmente dans les deux lignees cellulaires. Le blocage fonctionnel d'EMMPRIN par les cellules pretraitees par l'anticorps anti-EMMPRIN, avec et sans homocysteine, a nettement reduit l'expression de CD40 dans les deux lignees cellulaires comparativement au groupe temoin. Une epreuve a la dichlorodihydrofluoresceine a permis de demontrer une augmentation de la production de derives reactifs de l'oxygene dans les deux lignees cellulaires avec le traitement par l'homocysteine comparativement au groupe temoin. Conclusion: Nos resultats laissent entendre que l'hyperhomocysteinemie entrame une augmentation du nombre de macrophages du phenotype M1. Cet effet semble passer, au moins en partie, par une induction par l'EMMPRIN. [Traduit par la Redaction] Mots-cles: macrophage, M1, homocysteine, metalloproteinase matricielle-9, EMMPRIN, derives reactifs de l'oxygene.

Exercise: The forgotten medicine It has been well-established that regular exercise is associated with improvements in overall physical fitness, maintenance of health, a decreased risk of many disease states and, [...], Regular exercise is a great medicine with its benefits encompassing everything from prevention of cardiovascular risk to alleviation of different muscular myopathies. Interestingly, elevated levels of homocysteine (Hcy), also known as hyperhomocysteinemia (HHcy), antagonizes beta-2 adrenergic receptors ([β.sub.2]AR), gamma amino butyric acid (GABA), and peroxisome proliferator-activated receptor-gamma (PPARγ) receptors. HHcy also stimulates an elevation of the M1/M2 macrophage ratio, resulting in a more inflammatory profile. In this review we discuss several potential targets altered by HHcy that result in myopathy and excessive fat accumulation. Several of these HHcy mediated changes can be countered by exercise and culminate into mitigation of HHcy induced myopathy and metabolic syndrome. We suggest that exercise directly impacts levels of Hcy, matrix metalloproteinase 9 (MMP-9), macrophages, and G-protein coupled receptors (GPCRs, especially [G.sub.s]). While HHcy promotes the M1 macrophage phenotype, it appears that exercise may diminish the M1/M2 ratio, resulting in a less inflammatory phenotype. HHcy through its influence on GPCRs, specifically [β.sub.2]AR, PPARγ and GABA receptors, promotes accumulation of white fat, whereas exercise enhances the browning of white fat and counters HHcy-mediated effects on GPCRs. Alleviation of HHcy-associated pathologies with exercise also includes reversal of excessive MMP-9 activation. Moreover, exercise, by reducing plasma Hcy levels, may prevent skeletal muscle myopathy, improve exercise capacity and rescue the obese phenotype. The purpose of this review is to summarize the pathological conditions surrounding HHcy and to clarify the importance of regular exercise as a method of disease prevention. Key words: homocysteine, macrophage, exercise, cardiovascular, GPCR, MMP-9, skeletal muscle, PPAR. L'exercice regulier est une excellente medication dont les benefices vont de la prevention du risque cardiovasculaire au soulagement de differentes myopathies. Fait interessant, des niveaux eleves d'homocysteine (Hcy), aussi connus sous le terme d'hyperhomocysteinemie (HHcy), antagonisent les recepteurs beta 2 adrenergiques ([β.sub.2]AR), le recepteur de l'acide gamma amino butyrique (GABA : gamma amino butyric acid) et le recepteur active par les proliferateurs de peroxysomes gamma (PPARγ : peroxysome proliferator-activated receptor-gamma). La HHcy stimule aussi une elevation du ratio des macrophages M1/M2, resultant en un profil davantage inflammatoire. Dans cet article de revue, les auteurs discutent de differentes cibles potentielles modifiees par l'HHcy qui resultent en une myopathie et en une accumulation excessive de graisse. Plusieurs de ces changements operes par l'intermediaire de l'HHc peuvent etre contrecarres par l'exercice et ils culminent par une attenuation de la myopathie et du syndrome metabolique induits par l'HHcy. Les auteurs suggerent que l'exercice a un impact direct sur les niveaux d'Hcy, sur la metalloprotease de la matrice (MMP-9), les macrophages et les recepteurs couples aux proteines G (RCPG, notamment [G.sub.s]). Alors que l'HHcy favorise le phenotype M1 chez les macrophages, il semble que l'exercice puisse diminuer le ratio M1/M2, resultant en un phenotype moins inflammatoire. L'HHcy, par son influence sur les RCPG, notamment les recepteurs [β.sub.2]AR, PPARγ et GABA, favorise l'accumulation de graisse blanche, alors que l'exercice favorise la transformation de graisse blanche en graisse brune et contrecarre les effets de l'HHcy sur les RCPG. L'attenuation des pathologies associees a l'HHcy par l'exercice inclut aussi le renversement de l'activation excessive de MMP-9. De plus, l'exercice, en reduisant les niveaux plasmatiques de Hcy, peut prevenir la myopathie squelettique, ameliorer la capacite a l'exercice et venir en aide aux personnes obeses. Le but de cet article de revue est de resumer les conditions pathologiques qui entourent l'HHcy et de clarifier l'importance de l'exercice regulier comme methode de prevention de la maladie. [Traduit par la Redaction] Mots-cles : homocysteine, macrophage, exercice, cardiovasculaire, RCPG, MMP-9, muscle squelettique, PPAR.

Introduction Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, despite extensive research and clinical trials. The heart is a dynamic organ equipped with abundant mitochondria (Hom and [...], Therapeutic approaches for cardiac regenerative mechanisms have been explored over the past decade to target various cardiovascular diseases (CVD). Structural and functional aberrations of mitochondria have been observed in CVD. The significance of mitochondrial maturation and function in cardiomyocytes is distinguished by their attribution to embryonic stem cell differentiation into adult cardiomyocytes. An abnormal fission process has been implicated in heart failure, and treatment with mitochondrial division inhibitor 1 (Mdivi-1), a specific inhibitor of dynamin related protein-1 (Drp-1), has been shown to improve cardiac function. We recently observed that the ratio of mitofusin 2 (Mfn2; a fusion protein) and Drp-1 (a fission protein) was decreased during heart failure, suggesting increased mitophagy. Treatment with Mdivi-1 improved cardiac function by normalizing this ratio. Aberrant mitophagy and enhanced oxidative stress in the mitochondria contribute to abnormal activation of MMP-9, leading to degradation of the important gap junction protein connexin-43 (Cx-43) in the ventricular myocardium. Reduced Cx-43 levels were associated with increased fibrosis and ventricular dysfunction in heart failure. Treatment with Mdivi-1 restored MMP-9 and Cx-43 expression towards normal. In this review, we discuss mitochondrial dynamics, its relation to MMP-9 and Cx-43, and the therapeutic role of fission inhibition in heart failure. Key words: mitochondrial fission, fusion, Drp-1, Mfn2, Cx-43, MMP-9, pressure overload heart failure. Resume : Les approches therapeutiques aux mecanismes de regeneration cardiaque ont ete explorees au cours de la derniere decennie pour cibler differentes maladies cardiovasculaires (MCV). Des aberrations structurales et fonctionnelles de la mitochondrie ont ete observees dans les MCV. La pertinence de la maturation et de la fonction des mitochondries chez les cardiomyocytes se demarque par leur attribution a la differenciation des cellules souches embryonnaires en cardiomyocytes adultes. Un processus de fission anormal a ete implique dans l'insuffisance cardiaque, et un traitement avec un inhibiteur de la division mitochondriale 1 (Mdivi-1), un inhibiteur specifique de la protein Drp-1 (dynamin relatedprotein-1), s'est avere ameliorer la fonction cardiaque. Les auteurs ont recemment observe que le ratio de mitofusine 2 (Mfn2), une proteine de fusion, et de Drp-1, une proteine de fission, etait diminue lors de l'insuffisance cardiaque, suggerant un accroissement de la mitophagie, et qu'un traitement avec Mdivi-1 ameliorait la fonction cardiaque en ameliorant ce ratio. Une mitophagie anormale et un stress oxydant accru dans la mitochondrie contribuent a l'activation de MMP-9, conduisant a la degradation de Cx-43, une connexine importante des jonctions communicantes du myocarde ventriculaire. Des niveaux reduits de Cx-43 ont ete associes a une fibrose accrue et a une dysfonction ventriculaire dans l'insuffisance cardiaque. Le traitement avec Mdivi-1 retablissait l'expression de MMP-9 et de Cx-43 vers des niveaux normaux. Dans cet article de revue, les auteurs discutent de la dynamique mitochondriale, de sa relation a MMP-9 et a Cx-43, et du role therapeutique de l'inhibition de la fission dans l'insuffisance cardiaque. [Traduit par la Redaction] Mots-cles : fission mitochondriale, fusion, Drp-1, Mfn2, Cx-43, MMP-9, insuffisance cardiaque par surcharge de pression.

Although hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVD), there is a debate on whether HHcy is a risk factor or just a biomarker. Interestingly, homocysteine lowering strategies in humans had very little effect on reducing the cardiovascular risk, as compared with animals; this may suggest heterogeneity in human population and epigenetic alterations. Moreover, there are only few studies that suggest the idea that HHcy contributes to CVD in the presence of other risk factors such as inflammation, a known risk factor for CVD. Elevated levels of homocysteine have been shown to contribute to inflammation. Here, we highlight possible relationships between homocysteine, T cell immunity, and hypertension, and summarize the evidence that suggested these factors act together in increasing the risk for CVD. In light of this new evidence, we further propose that there is a need for evaluation of the causes of HHcy, defective remethylation or defective transsulfuration, which may differentially modulate hypertension progression, not just the homocysteine levels. [ABSTRACT FROM AUTHOR]

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