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Rational Pressure overload induces adaptive and maladaptive cardiac remodeling processes in the heart. Part of the maladaptive process is the cross-talk between cardiomyocytes and macrophages which is dependent on the function of the Activating Transcription Factor 3, ATF3. Yet, the molecular mechanism involved in cardiomyocytes-macrophages communication leading to macrophages recruitment to the heart and cardiac maladaptive remodeling is currently unknown. Methods and results Isolated peritoneal macrophages from either wild type or ATF3-KO mice were cultured in serum free medium to collect conditioned medium (CM). CM was used to probe an antibody cytokine/chemokine array. The interferon γ induced protein 10kDa, CXCL10, was found to be enriched in wild type macrophages CM. Wild type cardiomyocytes treated with CXCL10 in vitro, resulted in significant increase in cell volume as compared to ATF3-KO cardiomyocytes. In vivo, pressure overload was induced by phenylephrine (PE) infusion using micro-osmotic pumps. Consistently, CXCL11 (CXCL10 competitive agonist) and CXCL10 receptor antagonist (AMG487) attenuated PE-dependent maladaptive cardiac remodeling. Significantly, we show that the expression of the CXCL10 receptor, CXCR3, is suppressed in cardiomyocytes and macrophages derived from ATF3-KO mice. CXCR3 is positively regulated by ATF3 through an ATF3 transcription response element found in its proximal promoter. Finally, mice lacking CXCR3 display a significant reduction of cardiac remodeling processes following PE infusion. Conclusions Chronic PE infusion results in a unique cardiomyocytes-macrophages cross-talk that is mediated by IFNγ. Subsequently, macrophages that are recruited to the heart secrete CXCL10 resulting in maladaptive cardiac remodeling mediated by the CXCR3 receptor. ATF3-KO mice escape from PE-dependent maladaptive cardiac remodeling by suppressing the IFNγ-CXCL10-CXCR3 axis at multiple levels.

Rationale Pressure overload induces adaptive remodeling processes in the heart. However, when pressure overload persists, adaptive changes turn into maladaptive alterations leading to cardiac hypertrophy and heart failure. ATF3 is a stress inducible transcription factor that is transiently expressed following neuroendocrine stimulation. However, its role in chronic pressure overload dependent cardiac hypertrophy is currently unknown. Objective The objective of the study was to study the role of ATF3 in chronic pressure overload dependent cardiac remodeling processes. Methods and results Pressure overload was induced by phenylephrine (PE) mini-osmotic pumps in various mice models of whole body, cardiac specific, bone marrow (BM) specific and macrophage specific ATF3 ablations. We show that ATF3-KO mice exhibit a significantly reduced expression of cardiac remodeling markers following chronic pressure overload. Consistently, the lack of ATF3 specifically in either cardiomyocytes or BM derived cells blunts the hypertrophic response to PE infusion. A unique cross-talk between cardiomyocytes and macrophages was identified. Cardiomyocytes induce an ATF3 dependent induction of an inflammatory response leading to macrophage recruitment to the heart. Adoptive transfer of wild type macrophages, but not ATF3-KO derived macrophages, into wild type mice potentiates maladaptive response to PE infusion. Conclusions Collectively, this study places ATF3 as a key regulator in promoting pressure overload induced cardiac hypertrophy through a cross-talk between cardiomyocytes and macrophages. Inhibiting this cross-talk may serve as a useful approach to blunt maladaptive remodeling processes in the heart.

We thankYang et al. for their important comments regarding our recent manuscript “ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling” by Koren et al. [1]. We completely agree with the authors that the discrepancy can be explained by the different models used in the studies. Our analysis is based on the phenylephrine (PE) infusion pressure overload model and ATF3 transgenic mice. The results from these studies are consistent with ATF3's role in promoting cardiac hypertrophy [1,2]. In contrast, studies using the transverse aortic constriction (TAC) model suggest a cardio-protective role for ATF3 [3–6]. The opposing functions of ATF3 observed in the two models may be explained by the timing and duration of ATF3 expression. In the PE model, ATF3 expression is induced transiently and involves the recruitment of macrophages to the heart in an ATF3 dependent manner [1]. In the TAC model, whereas the involvement of immune cells is yet to be determined, persistent ATF3 expression appears as cardioprotective [3]. However, prolonged adult cardiac ATF3 expression displays maladaptive cardiac remodeling [2]. So how can constitutive ATF3 expression lead to opposite outcome? Previously, we showed that ATF3 may switch between either an inhibition or an activation mode, depending on the cellular context and protein partner, i.e. ATF3 inhibits transcription as a homodimer from TPA response elements, but activates transcription as a heterodimer with CHOP10 [7]. Revealing whether ATF3 exhibits differential transcriptional activity in the TAC, ATF3-transgenic mice and PE models may provide an explanation for the resulting diverse outcomes. Collectively, in mice models, ATF3 can play either a promoting or an inhibiting role in cardiacmaladaptive remodeling processes. Significantly