β-Catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation

Abstract

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 ...

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

“…Thus, we suggest that by inducing IGF1 and its muscle-specific splice variants, AR promotes the growth of muscle by activating the b-catenin pathway. Downregulation of b-catenin attenuates myocardial remodeling by promoting precursor cell differentiation, while upregulation induces precursor cell proliferation during muscle regeneration (Otto et al 2008, Perez-Ruiz et al 2008, Zelarayan et al 2008. Thus, these data are consistent with the current understanding of b-catenin in muscle remodeling.…”

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

“…77 Following experimental myocardial infarction in the mouse, b-catenin depletion attenuated post-infarct left ventricular remodeling, and significantly improved left ventricular function and survival. 80 Huang et al 81 demonstrated an association between Wnt signaling and post-infarct cardiac remodeling in aged mice. The cardiac detrimental role of Wnt/b-catenin signaling was further confirmed by the fact that b-catenin knockout attenuated phenylephrine-induced hypertrophy and upregulation of fetal genes in cardiomyocytes.…”

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

“…Consistently, inhibition of reactivated Wnt signaling has been shown to attenuate the hypertrophic responses (12)(13)(14). Although much has been studied about the role of Wnt signaling in cardiac hypertrophy and infarction, the regulatory mechanisms of Wnt signaling in cardiac remodeling is not fully understood.…”

“…Wnt signaling plays diverse roles in the control of proliferation and differentiation of cardiac progenitors during heart development (10) and in cardiac remodeling (11). Consistently, inhibition of Wnt signaling significantly reduces cardiac remodeling, postinfarct mortality, and cardiac function decline (12), whereas its activation causes a progressive dilated cardiomyopathy (13,14). Thus, modulation of Wnt signaling activity might be critical for prevention of maladaptive cardiac remodeling.…”