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On pathological stress, the heart reactivates several signaling pathways that traditionally were thought to be operational only in the developing heart. One of these pathways is the WNT signaling pathway. WNT controls heart development but is also modulated during adult heart remodeling. This review summarizes the currently available data regarding WNT signaling during left ventricular (LV) remodeling. Upstream, soluble frizzled-related proteins (sFRPs) block WNT-dependent activation of the canonical WNT pathway. By inhibition of WNT activation, these factors also reduce β-catenin-dependent transcription by altering the ratio of cytoplasmic/nuclear β-catenin. In experimental settings, sFRPs injected into the heart attenuated LV remodeling. sFRPs are secreted from autologous bone marrow-derived mononuclear cells. Disheveled is a signaling intermediate of both the canonical and noncanonical WNT pathway. Similarly to the effect of sFRP, depletion of a disheveled isoform attenuated LV remodeling. In contrast, disheveled activation led to progressive dilated cardiomyopathy. Inhibition of nuclear β-catenin signaling downstream of the canonical WNT pathway significantly reduced postinfarct mortality and functional decline of LV function following chronic left anterior descending coronary artery ligation. WNT signaling also affects mobilization and homing of bone marrow-derived vasculogenic progenitor cells. Finally, heart-specific WNT/β-catenin interaction partners have been identified that will possibly allow targeting this pathway in a tissue-specific manner. In summary, the WNT pathway plays a pivotal role in adult cardiac remodeling and may be suitable for therapeutic interventions. Currently, several molecular and cellular mechanisms whereby WNT inhibition attenuates LV remodeling are proposed. Reactivation of the developmental program to restore functional LV myocardium from resident precursor cells may significantly contribute to this process.

Aims: We have previously shown that cardiac-specific inhibition of NF-kappaB attenuates angiotensin II (AngII)-induced left ventricular (LV) hypertrophy in vivo. We now tested whether NF-kappaB inhibition is able to block LV remodelling upon chronic pressure overload and chronic AngII stimulation., Methods and Results: Cardiac-restricted NF-kappaB inhibition was achieved by expression of a stabilized IkappaBalpha mutant (IkappaBalphaDeltaN) in cells with an active alpha-myosin heavy chain (alphaMHC) promoter employing the Cre/lox technique. Upon low-gradient trans-aortic constriction (TAC, gradient 21 +/- 3 mmHg), hypertrophy was induced in both male and female control mice after 4 weeks. At this time, LV hypertrophy was blocked in transgenic (TG) male but not female mice with NF-kappaB inhibition. Amelioration of LV hypertrophy was associated with activation of NF-kappaB by dihydrotestosterone in isolated neonatal cardiomyocytes. LV remodelling was not attenuated by NF-kappaB inhibition after 8 weeks TAC, demonstrated by decreased fractional shortening (FS) in both control and TG mice irrespective of gender. Similar results were obtained when TAC was performed with higher gradients (48 +/- 4 mmHg). In TG mice, FS dropped to similar low levels over the same time course [FS sham, 29 +/- 1% (mean +/- SEM); FS control + 14 days TAC, 13 +/- 3%; FS TG + 14 days TAC, 9 +/- 5%]. Similarly, LV remodelling was accelerated by NF-kappaB inhibition in an AngII-dependent genetic heart failure model (AT1-R(alphaMHC)) associated with significantly increased cardiac fibrosis in double AT1-R(alphaMHC)/TG mice., Conclusion: 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.

We analyzed the effect of conditional, alphaMHC-dependent genetic beta-catenin depletion and stabilization on cardiac remodeling following experimental infarct. beta-Catenin depletion significantly improved 4-week survival and left ventricular (LV) function (fractional shortening: CT(Deltaex3-6): 24 +/- 1.9%; beta-cat(Deltaex3-6): 30.2 +/- 1.6%, P < 0.001). beta-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: beta-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 alphaMHC-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 (alphaMHC, 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 beta-catenin-depleted mice compared to cells isolated from control littermate demonstrated increased differentiation toward alpha-actin(pos) and cTnT(pos) cardiomyocytes after 10 days (CT(Deltaex3-6): 38.0 +/- 1.0% alpha-actin(pos); beta-cat(Deltaex3-6): 49.9 +/- 2.4% alpha-actin(pos), P < 0.001). We conclude that beta-catenin depletion attenuates postinfarct LV remodeling in part through increased differentiation of GATA4(pos)/Sca-1(pos) resident cardiac progenitor cells.

The adult heart has a uniform cellular response to adapt to injury after infarct or increased wall stress in chronic hypertension: hypertrophy of adult cardiomyocytes increases muscle fiber mass while at the same time apoptosis of cardiomyocytes may lead to further loss of contractile mass. The existence and quantitative amount of endogenous cardiac regeneration is currently under intense dispute, no clear picture has yet emerged. Recently, cardiac precursor cells and the signaling pathways controlling their differentiation in the adult organ have come into focus. In heart development, beta-catenin was identified to play a biphasic role in cardiomyocyte differentiation. While initially WNT/beta-catenin activation is required to commit mesenchymal cells to the cardiac lineage, downregulation of beta-catenin is needed for cardiomyocyte differentiation at later stages. Recent genetic data published by our lab suggest beta-catenin downregulation to be beneficial for adult cardiac remodeling. Here we discuss these data in the context of beta-catenin's role in adult cardiomyocyte hypertrophy, apoptosis and possibly regeneration.

The armadillo-related protein beta-catenin has multiple functions in cardiac tissue homeostasis: stabilization of beta-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell-cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of beta-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible alphaMHC-CrePR1 transgene was used to induce beta-catenin depletion (loxP-flanked exons 3 to 6, beta-cat(Deltaex3-6) mice) or stabilization (loxP-flanked exon 3, beta-cat(Deltaex3) mice). Levels of beta-catenin were altered both in membrane and nuclear extracts. Analysis of the beta-catenin target genes Axin2 and Tcf-4 confirmed increased beta-catenin-dependent transcription in beta-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. beta-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with beta-catenin depletion. In contrast, mice with stabilized beta-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing beta-catenin led to impaired fractional shortening compared with control littermates after Ang II stimulation. This functional deterioration was associated with altered expression of the T-box proteins Tbx5 and Tbx20 at baseline and after Ang II stimulation. In addition, atrophy-related protein IGFBP5 was upregulated in beta-catenin-stabilized mice. These data suggest that beta-catenin downregulation is required for adaptive cardiac hypertrophy.

We analyzed the effect of conditional, αMHC-dependent genetic β-catenin depletion and stabilization on cardiac remodeling following experimental infarct. β-Catenin depletion significantly improved 4-week survival and left ventricular (LV) function (fractional shortening: CT[supΔex3-6]:24 ± 1.9%; β-cat[supΔex3-6]: 30.2 ± 1.6%, P < 0.001). β-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: β-catenin-depleted mice showed a marked subendocardial and subepicardial layer of small cTnT[suppos] cardiomyocytes associated with increased expression of cardiac lineage markers TbxS and GATA4. Using a Cre-dependent IacZ reporter gene, we identified a noncardiomyocyte cell population affected by aMHCdriven 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 (αMHC, GATA4, Tbx5) but not cardiac Troponin T (cTnT). The cell population overlaps in part with both the previously described c-kit[suppos] and stem cell antigen-1 (Sca-1)[suppos] precursor cell population but not with the lslet-1[suppos] precursor cell pool. An in vitro coculture assay of highly enriched (>95%) Sca-1[suppos] cardiac precursor cells from β-catenin-depleted mice compared to cells isolated from control littermate demonstrated increased differentiation toward α-actin[suppos] and cTnT[suppos] cardiomyocytes after 10 days (CT[supΔex3-6]:38.0 ± 1.0% α-actin[suppos]; β-cat[supΔex3-6]: 49.9 ± 2.4% α-actin[suppos], P < 0.001). We conclude that β-catenin depletion attenuates postinfarct LV remodeling in part through increased differentiation of GATA4[suppos]/Sca-1[suppos] resident cardiac progenitor cells. [ABSTRACT FROM AUTHOR]