This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The underlying mechanism of heart failure is not well understood. Fibulin-2 is an extracellular matrix (ECM) protein that marks epithelial-mesenchymal transformation during embryonic cardiovascular development but is significantly down-regulated in the postnatal life. Fibulin-2 expression is remarkably up-regulated in myocardial wound healing, indicating its possible role in myocardial fibrosis and ventricular remodeling. Our working hypothesis is that Fibulin-2 intermediates upstream signals to induce ventricular remodeling. To test this hypothesis, Fibulin-2 null mutant mice (Fbln2-/-) were generated by gene targeting technique. Fbln2-/- showed no obvious phenotypic abnormalities compared with the wild type (WT) littermates and showed normal life span and fertility. (1) In vivo animal experiments: Both Fbln2-/- and WT were subject to myocardial infarction (MI) to induce heart failure. Hemodynamic, biochemical, and histological studies were performed to assess the biological role of fibulin-2 in ventricular remodeling after myocardial infarction. (2) In vitro newborn rat ventricular myocyte cell culture experiments: Ventricular myocytes are co-cultured with myocardial fibroblasts and are stimulated with angiotensin-II (Ang-II). The effects of Ang-II over changes in ECM, morphology and proliferation of cells are examined. Then the intrinsic fibulin-2 activity is inhibited by the fibulin-2 antibody to examine whether the neutralizations block the effect of Ang-II in ECM and cells. To date we found that the following: (1) Fbln2-/- resulted in better survival rate than WT at 2 weeks after MI (Fbln2-/- 78%, WT 44%). Although both revealed comparable myocardial hypertrophy, diastolic function was significantly well preserved in Fbln2-/-. Systolic function was better in Fbln2-/- than in WT. The degree of fibrosis is substantially decreased in Fbln2-/- myocardium; and (2) Ang-II increased fibulin-2 expression in a dose-responsive manner at 24 and 48 hours. Antibody blocking experiments will follow. In summary, absence of fibulin-2 preserved ventricular compliance despite comparable hypertrophy after MI. Our data suggest that fibulin-2 intermediates Ang-II related pathways in the formation of myocardial fibrosis and ventricular remodeling.
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