CIRC RES: Role of mast cells in abd aortic aneurysms

Posted by Borja.

(Circulation Research. 2008;102:1368.)

Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (+/+) rats following periaortic application of calcium chloride (CaCl2) treatment but not in the mast cell–deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E–deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA.

COMMENT:
In this paper, the authors prove, in a mouse model of AAA (abdominal aorta aneurysm), that mast cells are required for the development of AAA. Mast cells have been implicated in various pathjological proccessess, mainly in those in which inflammation is exacerbated.
It would be really interesting to know whether mast cells are also involved in the development of LV aneurysms (i.e. post-MI). Maybe, those patients showing aneurismatic remodelling of the LV post-MI have a increase in the degranulation of mast cells (potentially treatable condition).
If this is interesting for the gang, we could discuss a pilot study in the pig model of MI (Hans can take the "alternativa" in the tuesdays 7am meetings)........

CIRC RES PAPER: Tbx family in conduction system development

Posted by Hans.

(Circulation Research. 2008;102:1340.)

Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System.


The cardiac conduction system consists of distinctive heart muscle cells that initiate and propagate the electric impulse required for coordinated contraction. The conduction system expresses the transcriptional repressor Tbx3, which is required for vertebrate development and controls the formation of the sinus node. In humans, mutations in Tbx3 cause ulnar–mammary syndrome. Here, we investigated the role of Tbx3 in the molecular specification of the atrioventricular conduction system. Expression analysis revealed early delineation of the atrioventricular bundle and proximal bundle branches by Tbx3 expression in human, mouse, and chicken. Tbx3-deficient mice, which die between embryonic day 12.5 and 15.5, ectopically expressed genes for connexin (Cx)43, atrial natriuretic factor (Nppa), Tbx18, and Tbx20 in the atrioventricular bundle and proximal bundle branches. Cx40 was precociously upregulated in the atrioventricular bundle of Tbx3 mutants. Moreover, the atrioventricular bundle and branches failed to exit the cell cycle in Tbx3 mutant embryos. Finally, Tbx3-deficient embryos developed outflow tract malformations and ventricular septal defects. These data reveal that Tbx3 is required for the molecular specification of the atrioventricular bundle and bundle branches and for the development of the ventricular septum and outflow tract. Our data suggest a mechanism in which Tbx3 represses differentiation into ventricular working myocardium, thereby imposing the conduction system phenotype on cells within its expression domain.

COMMENTS:
Tbx is a family of development represors. Their role in heart development is to block the differentiation of conduction cells into working myocardium. Hence, when Tbx (3 in this case) is absent, the cells continue their lineage becoming working myocardium, with the subsequent absence of sinus or AV node cells.
Tbx has been also implicated in the development of interventricular septum and RV outflow tract.