Tumor necrosis factor (TNF) is upregulated in a number of cardiomyopathies. This thesis investigates TNF in triggering the expression and activation of matrix metalloproteinases (MMPs) in pressure overload cardiac disease, and explores the role of superoxide. Cardiac pressure overload was generated in adult wild-type and TNF-/- mice by transverse aortic constriction. Isolated cardiomyocytes and cardiofibroblasts from neonatal mice ventricles were treated with recombinant TNF (rTNF), and MMP induction and activation were assessed, with and without apocynin (a NADPH-oxidase inhibitor). TNF-/- mice showed less superoxide production and MMP activation, compared to wild-type mice, following pressure overload. rTNF upregulated the production of NADPH-dependent superoxide in cardiomyocytes as early as 1 hour (24 hours in cardiofibroblasts). rTNF also increased the expression of MMP-9 and MMP-12 in cardiomyocytes more than in cardiofibroblasts, and MMP-8 and MMP-13 more in cardiofibroblasts. This induction in both cardiac cell types was concomitant with superoxide production.

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La première phase pour la fibrose réparatrice après un infarctus du myocarde (IM) est la réponse inflammatoire. Sans inflammation, la cicatrisation est perturbée ce qui provoquerait la rupture du myocarde. Une forte réponse inflammatoire peut mener à une rupture en raison d’une dégradation excessive de la matrice extracellulaire. Afin d’améliorer le pronostic des patients, des techniques pour contrôler la réponse inflammatoire sont recherchées. En réponse au stress, MK2 (MAP kinase-activated protein kinase-2) est activée par p38α et β. Cette kinase régule l’inflammation en stabilisant l’ARNm de cytokines. Les souris où MK2 est inactivée (MK2-/-) présentent une diminution de l’expression des cytokines après l’injection de lipopolysaccharides. L’objectif de l’étude était de déterminer si l’absence de MK2 altérerait l’inflammation post-IM provoqué par la ligature permanente de l’artère interventriculaire antérieure chez des souris mâles MK2+/+ et MK2-/-. Cette étude démontre une réduction significative de mortalité chez les souris MK2-/-. Les échocardiographies ont révélé une altération similaire des fonctions cardiaques chez les souris MK2+/+ et MK2-/-, mais la structure était moins affectée chez les souris MK2-/-. La coloration au trichrome de Masson n’a démontré aucune différence pour la taille de la cicatrice ou la quantité de collagène. Aucune différence n’a été remarquée dans le recrutement des leucocytes. L’utilisation d’un RT2 Profiler PCR Array spécifique aux cytokines a démontré que l’abondance d’ARNm tend à être réduite dans les tissus sains MK2-/-, mais l’inflammation n’était pas réduite comparativement aux souris MK2+/+. En conclusion, MK2 ne semble pas essentielle à la réponse inflammatoire post-IM dans le coeur des souris. / The first phase of reparative fibrosis following a myocardial infarct (MI) is an inflammatory response. Without inflammation, scar formation is impaired, which leads to heart rupture. A strong response can also lead to heart rupture due to excessive ECM degradation. Efficient ways of controlling inflammation are constantly being explored to improve the prognosis in patients. In response to cellular stress, MAP kinase-activated protein kinase-2 (MK2) is activated by p38α and β. This protein serine/threonine kinase mediates the inflammatory process by stabilising pro-inflammatory cytokine mRNA. MK2-deficent mice (MK2-/-) show an impaired expression of cytokines, such as IL-1β and IL-6, in response to lipopolysaccharide injection. The objective of this study was to determine if the absence of MK2 impaired the inflammatory phase following an MI induced by permanent ligation of the left anterior descending artery (LADL) in 12-week-old male MK2+/+ and MK2-/- litter mate mice. This study shows that mortality was significantly reduced in MK2-/- mice. Echocardiographic imaging showed that heart function was affected in similar ways in MK2+/+ and MK2-/- mice whereas heart structure was less affected MK2-/- mice. Masson's trichrome staining revealed no difference in scar size and collagen content. No differences were observed in neutrophil and macrophage recruitment. The use of a RT2 Profiler PCR Array specific to cytokines showed that mRNA fold expression appeared to be reduced in MK2-/- healthy tissues but that the inflammatory response was not impaired. In conclusion, MK2 was not essential for the inflammatory phase of post-MI wound repair in the male mouse heart.