Abstract

Infusion of bone marrow-derived mononuclear cells (BMMNC) has been reported to ameliorate cardiac dysfunction after acute myocardial infarction. In this study, we investigated whether infusion of BMMNC is also effective for non-ischemic heart failure model mice and the underlying mechanisms. Intravenous infusion of BMMNC showed transient cardioprotective effects on animal models with dilated cardiomyopathy (DCM) without their engraftment in heart, suggesting that BMMNC infusion improves cardiac function via humoral factors rather than their differentiation into cardiomyocytes. Using conditioned media from sorted BMMNC, we found that the cardioprotective effects were mediated by growth hormone (GH) secreted from myeloid (Gr-1(+)) cells and the effects was partially mediated by signal transducer and activator of transcription 3 in cardiomyocytes. On the other hand, the GH expression in Gr-1(+) cells was significantly downregulated in DCM mice compared with that in healthy control, suggesting that the environmental cue in heart failure might suppress the Gr-1(+) cells function. Activin A was upregulated in the serum of DCM models and induced downregulation of GH levels in Gr-1(+) cells and serum. Furthermore, humoral factors upregulated in heart failure including angiotensin II upregulated activin A in peripheral blood mononuclear cells (PBMNC) via activation of NFκB. Similarly, serum activin A levels were also significantly higher in DCM patients with heart failure than in healthy subjects and the GH levels in conditioned medium from PBMNC of DCM patients were lower than that in healthy subjects. Inhibition of activin A increased serum GH levels and improved cardiac function of DCM model mice. These results suggest that activin A causes heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure.

Highlights

  • Heart failure is a major cause of mortality in many countries

  • We observed the improvement of cardiac function of dilated cardiomyopathy (DCM) model mice by bone marrow-derived mononuclear cells (BMMNC) infusion, no engraftment of infused BMMNC was observed in the heart

  • The growth and protection of cardiomyocytes are regulated by various kinases such as Akt, extracellular signal-regulated kinase (Erk) and Janus kinase (Jak)/signal transducers and activators of transcription (Stat), and many studies have demonstrated that activation of Akt and Erk induces cardiac hypertrophy [25], [26] and prevents cardiomyocytes from stress-induced apoptosis [27]

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Summary

Introduction

Infusion of bone marrow-derived mononuclear cells (BMMNC) is expected as a novel treatment of heart failure. The outcomes vary among trials, recent meta-analyses revealed that cardiac function slightly improves following BMMNC infusion for ischemic heart diseases [5], [6]. Bone marrow cells were reported to be incorporated into the damaged myocardium and to differentiate into various cell types including cardiomyocytes [7]. Whether bone marrowderived stem cells can differentiate into many cardiomyocytes is still an open question [8]. There are many reports indicating that transplantation of various types of stem cells improves the cardiac function of ischemic hearts, mainly by paracrine factors which induce angiogenesis and cardioprotection [9]–[11]. Since the effects of BMMNC infusion for non-ischemic cardiomyopathy remain unknown, we examined whether BMMNC infusion improves cardiac function of non-ischemic cardiomyopathy

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