Increased prostaglandin-D2 in male STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Abstract

Cardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency conditional knockout (CKO) display premature age-related heart failure associated with reduced cardiac capillary density. In the present study, isolated male and female CKO-cardiomyocytes exhibit increased prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male cardiomyocytes, which is associated with increased prostaglandin D2 (PGD2) secretion from isolated male but not female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from impaired androgen receptor (AR)–signaling due to loss of its cofactor STAT3. Elevated PGD2 secretion in males is associated with increased white adipocyte accumulation in aged male but not female hearts. Adipocyte differentiation is enhanced in isolated stem cell antigen-1 (SCA-1)+ cardiac progenitor cells (CPC) from young male CKO-mice compared with the adipocyte differentiation of male wild-type (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and hypomethylation in the white adipocyte differentiation gene Zfp423 associated with up-regulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation compared with WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in male CKO-CPC compared with male WT-CPC, whereas no differences in the EZH2 expression in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD2 stimulation reduces the expression of EZH2, thereby up-regulating ZFP423 expression and promoting white adipocyte differentiation. The treatment of young male CKO mice with the COX inhibitor Ibuprofen or the PGD2 receptor (DP)2 receptor antagonist BAY-u 3405 in vivo increased EZH2 expression and reduced ZFP423 expression and adipocyte differentiation in CKO-CPC. Thus, cardiomyocyte STAT3 deficiency leads to age-related and sex-specific cardiac remodeling and failure in part due to sex-specific alterations in PGD2 secretion and subsequent epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired AR signaling in absence of STAT3, which reduces the expression of the PG-degrading enzyme HPGD.

Changes in the Left Ventricular Eicosanoid Profile in Human Dilated Cardiomyopathy

“…Chronic inflammation underlies many forms of CVD ( 28 ). Administration of exogenous prostaglandins promotes a DCM-like phenotype of cardiomyocytes which further perpetuates prostaglandin secretion ( 32 , 33 ). Thus, a self-sustaining pro-inflammatory environment exists within the human DCM heart.…”

“…Some studies suggest differences in eicosanoid production and metabolism could explain sex-dependent differences in CVD risk and severity ( 47 ). Indeed, male DCM patients have been shown to have higher serum prostaglandin concentrations, which may suggest a greater involvement of pro-inflammatory eicosanoid signaling in male DCM patients ( 32 ). Apparent sex differences in EpFA:diol ratios may be attributed to higher expression of CYP2J2 in male DCM hearts, which did not reach significance in females.…”

Increased Epoxyeicosatrienoic Acids and Hydroxyeicosatetraenoic Acids After Treatment of Iodide Intake Adjustment and 1,25-Dihydroxy-Vitamin D3 Supplementation in High Iodide Intake–Induced Hypothyroid Offspring Rats

“…PGJ2 is formed by dehydration within the cyclopentenone ring of PGD2 (Abdelrahman et al, 2004 ). Stelling et al ( 2020 ) reported that the PGD2 level was significantly increased in male mice cardiomyocytes with a cardiomyocyte-specific transcription factor-3 (STAT3) deficiency conditional knockout (CKO), which is an impairment of the endogenous cardiac regeneration potential as it shifts the differentiation potential of the cardiac progenitor cell (CPC) pool from endothelial cells toward white adipocytes, thereby promoting heart failure, a condition that impairs androgen receptor (AR) signaling in the absence of STAT3, which reduces the expression of the PG-degrading enzyme 15-hydroxyprostaglandin-dehydrogenase (HPGD). HDoHEs are biosynthesized from DHA, and the function is still not clearly elucidated.…”

Administration of Gas6 attenuates lung fibrosis via inhibition of the epithelial-mesenchymal transition and fibroblast activation

“…(Yoon et al 2016 ), or BAY-u3405 (30 mg/kg, i.o.) (Stelling et al 2020 ) was administered at the same time as rGas6 1 day before BLM treatment. The inhibitor was administered once daily (AH-6809) or every two days (BGB324, NS-398, and BAY-u3405) following the first dosage, and mice were sacrificed 14 days after BLM treatment.…”