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 ...

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AimsThe role of nitric oxide (NO) in heart failure (HF) is complex and remains controversial. We tested the hypothesis that the role of NO in isolated atria and cardiomyocytes is altered in isoproterenol-induced HF. Methods and resultsRats received isoproterenol (ISO, 5 mg/kg/day, intraperitoneally) or vehicle for 1 week. Haemodynamic parameters were obtained by left ventricular catheterization. Effects of NOS inhibition on isolated atria and on electrically paced left ventricular myocytes were determined. Additionally, expressions of nitric oxide synthases and their allosteric modulators hsp90, caveolin-1, and caveolin-3 proteins in the left ventricles were measured. ISO increased left ventricular mass by 33% and decreased indices of left ventricular systolic and diastolic function dp/dt min and dp/dt max (both P , 0.05). Isolated atria from HF rats had a lower spontaneous beating rate (P , 0.05). NOS inhibition by L-NAME increased basal frequency and attenuated the positive chronotropic effect of beta-adrenergic stimulation in the HF group (P , 0.05). Ventricular myocytes from failing hearts had impaired cell shortening. L-NAME decreased contractility of control, but not failing myocytes. Left ventricular expressions of eNOS, hsp90, iNOS, but not nNOS or caveolins, were increased. ConclusionDespite the increased capacity for NO synthesis in isoproterenol-induced HF, NO does not sustain contractility of failing myocytes. NO may contribute to the decreased basal heart rate and it may accelerate beta-adrenergic stimulation of chronotropy.--

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