Increased prostaglandin-D₂in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Abstract

31 Cardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline 32 with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency (CKO) 33 display premature age-related heart failure associated with reduced cardiac capillary density.34 In the present study isolated male and female CKO-cardiomyocytes exhibit increased 35 prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading 36 hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male 37 cardiomyocytes, which is associated with increased PGD 2 secretion from isolated male but not 38 female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from 39 impaired androgen-receptor-(AR)-signaling due to loss of its co-factor STAT3. Elevated PGD 2 40 secretion in males is associated with increased white adipocyte accumulation in aged male 41 but not female hearts. Adipocyte differentiation is enhanced in isolated SCA-1 + -cardiac-42 progenitor-cells (CPC) from young male CKO-mice compared to the adipocyte differentiation 43 of male wildtype (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly 44 isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and 45 hypomethylation in the white adipocyte differentiation gene Zfp423 associated with 46 upregulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation 47 compared to WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in 48 male CKO-CPC compared to male WT-CPC whereas no differences in the EZH2 expression 49 in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells 50 or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is 51 sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD 2 52 stimulation reduces the expression of EZH2 thereby upregulating ZFP423 expression and 53 promoting white adipocyte differentiation.54 Thus, cardiomyocyte STAT3-deficiency leads to age-related and sex-specific cardiac 55 remodeling and failure in part due to sex-specific alterations in PGD 2 secretion and subsequent 56 epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired 3 57 AR signaling in absence of STAT3, which reduces the expression of the PG degrading enzyme 58 HPGD. 59 4 60 Introduction 61 Men and women experience quite different cardiovascular disease susceptibility profiles and 62 outcome, a feature that is poorly understood. Further, the effects of biologic sex on health, 63 disease susceptibility and mortality are vastly understudied (1, 2). Recent studies showed that 64 genetics contribute to sex-specific differences in fat tissue and cardiovascular and metabolic 65 diseases (3). Pathophysiologically enhanced cardiac fat content is frequently observed in 66 patients with heart failure, in arrhythmogenic right ventricular dysplasia (ARVD), and after 67 ...