We analyzed the effect of conditional, ␣MHC-dependent genetic ␤-catenin depletion and stabilization on cardiac remodeling following experimental infarct. ␤-Catenin depletion significantly improved 4-week survival and left ventricular (LV) function (fractional shortening: CT ⌬ex3-6 : 24 ؎ 1.9%; ␤-cat ⌬ex3-6 : 30.2 ؎ 1.6%, P < 0.001). ␤-Catenin stabilization had opposite effects. No significant changes in adult cardiomyocyte survival or hypertrophy were observed in either transgenic line. Associated with the functional improvement, LV scar cellularity was altered: ␤-catenin-depleted mice showed a marked subendocardial and subepicardial layer of small cTnT pos cardiomyocytes associated with increased expression of cardiac lineage markers Tbx5 and GATA4. Using a Cre-dependent lacZ reporter gene, we identified a noncardiomyocyte cell population affected by ␣MHC-driven gene recombination localized to these tissue compartments at baseline. These cells were found to be cardiac progenitor cells since they coexpressed markers of proliferation (Ki67) and the cardiomyocyte lineage (␣MHC, GATA4, Tbx5) but not cardiac Troponin T (cTnT). The cell population overlaps in part with both the previously described c-kit pos and stem cell antigen-1 (Sca-1) pos precursor cell population but not with the Islet-1 pos precursor cell pool. An in vitro coculture assay of highly enriched (>95%) Sca-1 pos cardiac precursor cells from ␤-catenin-depleted mice compared to cells isolated from control littermate demonstrated increased differentiation toward ␣-actin pos and cTnT pos cardiomyocytes after 10 days (CT ⌬ex3-6 : 38.0 ؎ 1.0% ␣-actin pos ; ␤-cat ⌬ex3-6 : 49.9 ؎ 2.4% ␣-actin pos , P < 0.001). We conclude that ␤-catenin depletion attenuates postinfarct LV remodeling in part through increased differentiation of GATA4 pos /Sca-1 pos resident cardiac progenitor cells. D espite adaptive mechanisms including activation of cardiomyocyte survival pathways and hypertrophy, left ventricular (LV) remodeling often progresses to cardiac dilation and heart failure (1). Recently, the quantitative contribution of endogenous cardiac regeneration was found to account for at least 25% of cardiomyocytes in the infarct border zone (2). However, essential characteristics of this cardiac precursor cell pool, like signaling pathways directing differentiation and/or proliferation, are largely unknown.Transcription factors essential for embryonic cardiac development also affect adult cardiac remodeling in mice (3). Regulation of the Wnt/␤-catenin pathway differentially regulates embryonic cardiac progenitor cells prespecification, renewal, and differentiation in the cardiac mesoderm (4-7). Activation of the Wnt/␤-catenin pathway specifically stimulates Islet-1 cardiac progenitor cells proliferation while delaying differentiation. Conversely, increased expression of Wnt signaling inhibitors in ␣MHC pos cardiac precursor cells isolated from embryoid bodies lead to increased cardiomyocyte differentiation (8).We previously reported that downregulation of ␤-catenin in ...

NF-kappaB inhibition attenuates cardiac hypertrophy in a gender-specific manner but does not alter the course of stress-induced LV remodelling, indicating NF-kappaB to be required for adaptive cardiac hypertrophy.

Wnt/β-catenin signalling controls adult heart remodelling in part via regulation of cardiac progenitor cell (CPC) differentiation. An enhanced understanding of mechanisms controlling CPC biology might facilitate the development of new therapeutic strategies in heart failure. We identified and characterized a novel cardiac interaction between Krueppel-like factor 15 and components of the Wnt/β-catenin pathway leading to inhibition of transcription. In vitro mutation, reporter assays and co-localization analyses revealed that KLF15 requires both the C-terminus, necessary for nuclear localization, and a minimal N-terminal regulatory region to inhibit transcription. In line with this, functional Klf15 knock-out mice exhibited cardiac β-catenin transcriptional activation along with functional cardiac deterioration in normal homeostasis and upon hypertrophy. We further provide in vivo and in vitro evidences for preferential endothelial lineage differentiation of CPCs upon KLF15 deletion. Via inhibition of β-catenin transcription, KLF15 controls CPC homeostasis in the adult heart similar to embryonic cardiogenesis. This knowledge may provide a tool for reactivation of this apparently dormant CPC population in the adult heart and thus be an attractive approach to enhance endogenous cardiac repair.